JADICELL -Mesenchymal Stem Cells: A New Piece in the Puzzle of COVID-19 Treatment

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curncman
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JADICELL -Mesenchymal Stem Cells: A New Piece in the Puzzle of COVID-19 Treatment

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Mesenchymal Stem Cells: A New Piece in the Puzzle of COVID-19 Treatment

https://www.frontiersin.org/articles/10 ... 01563/full


Felipe Saldanha-Araujo1,2, Emãnuella Melgaço Garcez3, Amandda Evelin Silva-Carvalho1 and Juliana Lott Carvalho3,4*
1Hematology and Stem Cells Laboratory, Health Sciences Department, University of Brasília, Brasilia, Brazil
2Molecular Pharmacology Laboratory, Health Sciences Department, University of Brasília, Brasilia, Brazil
3Multidisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Brasilia, Brasilia, Brazil
4Genomic Sciences and Biotechnology Program, Catholic University of Brasília, Brasilia, Brazil
COVID-19 is a disease characterized by a strong inflammatory response in severe cases, which fails to respond to corticosteroid therapy. In the context of the current COVID-19 outbreak and the critical information gaps regarding the disease, several different therapeutic strategies are under investigation, including the use of stem cells. In the present manuscript, we provide an analysis of the rationale underlying the application of stem cells to manage COVID-19, and also a comprehensive compendium of the 69 clinical trials underway worldwide aiming to investigate the application of stem cells to treat COVID-19. Even though data are still scarce, it is already possible to observe the protagonism of China in testing mesenchymal stem cells (MSCs) for COVID-19. Furthermore, it is possible to determine that current efforts focus on the use of multiple infusions of high numbers of stem cells and derived products, as well as to acknowledge the positive results obtained by independent groups who publicized the therapeutic benefits provided by such therapies in 51 COVID-19 patients. In such a rapid-paced field, up-to-date systematic studies and meta-analysis will aid the scientific community to separate hype from hope and offer an unbiased position to the society and governments.
curncman
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Review of Trials Currently Testing Stem Cells for Treatment of Respiratory Diseases: Facts Known to Date and Possible Ap

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Review of Trials Currently Testing Stem Cells for Treatment of Respiratory Diseases: Facts Known to Date and Possible Applications to COVID-19

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442550/

Abstract
Therapeutic clinical and preclinical studies using cultured cells are on the rise, especially now that the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a “public health emergency of international concern”, in January, 2020. Thus, this study aims to review the outcomes of ongoing clinical studies on stem cells in Severe Acute Respiratory Syndrome (SARS), Acute Respiratory Distress Syndrome (ARDS), and Middle East Respiratory Syndrome (MERS). The results will be associated with possible applications to COVID-19. Only three clinical trials related to stem cells are considered complete, whereby two are in Phase 1 and one is in Phase 2. Basically, the ongoing studies on coronavirus are using mesenchymal stem cells (MSCs) derived from bone marrow or the umbilical cord to demonstrate their feasibility, safety, and tolerability. The studies not related to coronavirus are all in ARDS conditions; four of them are in Phase 1 and three in Phase 2. With the COVID-19 boom, many clinical trials are being carried out using different sources with an emphasis on MSC-based therapy used to inhibit inflammation. One of the biggest challenges in the current treatment of COVID-19 is the cytokine storm, however MSCs can prevent or mitigate this cytokine storm through their immunomodulatory capacity. We look forward to the results of the ongoing clinical trials to find a treatment for the disease. Researchers around the world are joining forces to help fight COVID-19. Stem cells used in the current clinical studies are a new therapeutic promise for COVID-19 where pharmacological treatments seem insufficient.

Stem Cells and Respiratory Diseases
Stem cells are specialized cells that differentiate into other cell types [7]. In certain organs, the stem cells produce descendants that maintain tissue homeostasis and also have the same function as the cells that are not generated from this differentiation [8]. This class of cells depicts a revolution in such studies enabling their application in patients with various disorders, including lung diseases, thus allowing to study cell-based therapies for their treatment. For the treatment of ARDS and sepsis, various cell types are used such as headStartembryonic stem cellsheadEnd (ESCs), headStartmesenchymal stem cellsheadEnd (MSCs), and epithelial progenitor cells (EpPCs). Currently, most of the preclinical studies are using MSCs, though headStartinduced pluripotent stem cellsheadEnd (iPSC) for the treatment of ARDS [9] are also being used.

The lungs were previously thought to be “post-mitotic” and unable to regenerate, while the stem cell populations, such as bone marrow, intestinal mucosa, and skin are considered regenerative. Yet it is known that different regions in the lungs are dependent on different cell populations, such as the endogenous stem cell complex for tissue repair demonstrating regenerative characteristics [10]. For example, idiopathic pulmonary fibrosis (IPF) is a fatal form of the disease characterized by scar tissue formation in the interstitial lungs with extracellular matrix deposited over time. The symptoms include cough, exertional dyspnea, functional and exercise limitation, acute respiratory failure, and death.

With the emergence of stem cell therapy in treating diseases, the murine bleomycin model became the best-characterized one, in which the administration of allogeneic bone marrow-derived-MSCs (BM-MSCs) reduces inflammation and collagen deposition [11–13]. Also, it was observed that stem cells from the placenta and human umbilical cord demonstrated reduced lung tissue damage in the mouse bleomycin models [14–16].

Another example of stem cells applied to lung disease is chronic obstructive pulmonary disease (COPD), a major devastating disease worldwide. COPD is characterized by chronic small airway inflammation, commonly known as chronic bronchitis, causing progressive poor airflow leading to damage of lung tissues (emphysema). MSCs, as a therapy, are considered a strong candidate in headStartclinical trialsheadEnd to repair damaged lung tissue in COPD or any other chronic lung disease [17–19].

Stem cells, particularly pluripotent cells such as ESCs or iPSCs, offer the potential to differentiate into lung cells reprogramming the immune response to reduce destructive inflammatory elements and directly replace damaged cells and tissues [20]. Thus, it can be a promising novel therapeutic strategy in ARDS to repair and resolve a lung injury restoring the whole epithelial and endothelial function [21]. They can also attenuate bacterial sepsis, directly associated with ARDS, via several mechanisms, such as improving the phagocytic ability, secreting anti-microbial peptides [22], and increasing bacterial clearance [23]. Furthermore, MSCs demonstrated a great potential when reducing the endotoxin-induced injury to explanted human lungs [24].

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Mesenchymal Stem Cells
headStartMesenchymal stem cellsheadEnd can be isolated from bone marrow and expanded extensively in vitro. They play an important role in the repair process or may engraft the injured lung [25, 26]. Engraftment may initiate simultaneously, where MSCs differentiate into lung epithelial cells and can directly replace the damaged cells in alveoli during the treatment of ARDS [27, 28]. Their applicability has been reported in treating cardiovascular and pulmonary diseases [26, 29] along with severe inflammation [30, 31]. These properties are also very attractive due to the immunosuppressive/immunomodulatory abilities [32, 33] influencing an increase in Keratinocyte growth factor (KGF) on epithelial cells, and in the study models of lung injury. Thus, they play a protective role in inducing type II cell proliferation and edema clearance [34]. Additionally, KGF could upregulate alveolar fluid clearance in ex vivo human lungs injured by an endotoxin [24]. MSCs play an anti-inflammatory role secreting several mediators that down-regulate the inflammatory process [35] and secrete growth factors, including KGF [36, 37].

In animal models with lung injury, intravenous MSCs led to favorable outcomes, such as reduction in inflammation, pro-inflammatory cytokines, and lung edema [38]. In mouse models, the treatment involving MSCs reduced pulmonary edema and extended survival in Escherichia coli endotoxin-induced lung injury [39]. The outcomes of involving MSCs in experimental models of ALI/ARDS have been promising as a cell-based therapy [40].

Previously, ARDS was defined within two simple concepts, namely [1] the pro-inflammatory (leading to host damage) and [2] fibrotic (repair and fibrosis) phase. These two phases make the disease progression more complex [41]. Moreover, the mechanism of action of MSCs is also unknown due to the diverse array of paracrine mediators which are directly associated with the therapeutic effects [42]. Several factors that influence these effects are [1] differences between the cell surface epitopes and genomic stability between mice and humans involved in the studies [43]; [2] different inflammatory environment [44]; and [3] the heterogeneity of MSCs and their subtypes [45]. However, the complete success of MSCs as a cell therapy for patients with ARDS will probably depend on a better understanding of their mechanism of action and on defining the best strategies for their use in a clinical setting [46].

The benefit of MSCs utilization is directly related to paracrine soluble factors, transfer of mitochondria, and histologically active microvesicles [47]. siRNA knockdown was utilized to analyze the paracrine soluble factors in cultured human type 2 cells during in vitro MSCs treatment and it was found that angiopoietin-1 secretion was partially responsible for the beneficial effect of MSCs [48–50]. The presence of MSCs upregulates lipoxin A4, a pro-resolving lipid mediator which could play an important role in MSC-mediated healing of lung injury [49, 50]. Additionally, MSCs mediate the release of microvesicles during cell-to-cell communication [51].

The resistance of pulmonary epithelial cells during inflammation is an important tool to combat pulmonary edema. The interaction between epithelial cells and MSCs in an inflammatory process represents a critical information point in revealing the mechanism of MSC-mediated therapeutic effects, thus allowing to design a better practical protocol to manage these cells [52]. However, the genetic manipulation to improve the therapeutic efficacy of MSCs, so that they could work at the low level of trophic factors in the damaged host tissue, remains a permanent challenge [53].

MSCs-derived Microvesicles
Among the MSC-derived extracellular vesicles (EVs) or microvesicles, the best- characterized ones are the exosomes. They have a conserved protein group known as tetraspanins which is important for cell targeting. These vesicles are rich in integrins, flotillins (lipid raft-associated), and cholesterol [54]. An important role of microvesicles is cell-cell-mediated communication and they are composed of small circular membrane fragments released from the endosomal cell membrane [33, 55]. MSC-derived EVs contain RNAs that are involved in transcription control, cell proliferation, and immune regulation [56], and interact using different mechanisms with the cell surface receptors [54, 57]. These exosomes activate molecules between the cells through the transfer of genetic material and specific organelles such as mitochondria [58]. Microvesicles derived from MSCs play an important role in the repair of lung injury in ARDS [59]. Zhu et al. [51] observed a decrease in lung edema and neutrophil counts by utilizing microvesicles from human bone marrow MSCs with an increased expression of KGF in this induced lung injury. Evidence from several studies supports the role of microvesicles in cell-based therapies associated with respiratory diseases [55, 60]. Furthermore, microvesicles from adult MSCs protect against acute tubular injury ischemia–reperfusion-induced acute and chronic kidney injury [61, 62].

In relation to cell-free therapeutics in lung diseases, Monsel et al. [63] displayed various advantages of using MSC-derived extracellular vesicles compared to the MSCs. The advantages are as follows: they are non-self-replicating, have reduced risk of iatrogenic tumor formation, can be stored without DMSO at − 80ºC to maintain a biologically active state, they do not express MHC I or II antigens, nor can be induced to express them, and they allow allogeneic transplantation.

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Stem Cells From Other Sources
Induced Pluripotent Stem Cells
The headStartinduced pluripotent stem cellsheadEnd (iPSCs) produced by the method of Takahashi & Yamanaka [64] are based on the reprogramming of adult cells to a “stem cell state” through a gene transfection technique by manipulating them to undergo cellular differentiation, plasticity and behavioral transformation [64, 65].

There is a great potential of using iPSCs in ARDS and sepsis [9]. However, the associated problems arising from their use are unclear, and also their low efficiency during differentiation and the reprogramming process might be a concern. Thus, a possible genomic modification may be considered to address these drawbacks [66].

Embryonic Stem Cells
The human headStartembryonic stem cellsheadEnd (ESCs) derived from the inner cell mass of blastocysts are pluripotent and able to differentiate into all three primary germ layers. Their capacity to self-renew makes them a viable treatment option for tissue regeneration [67]. These ESCs promote the MSCs through reprogramming and differentiation with demonstrated efficacy in murine endotoxin and bleomycin-induced lung injury [68]. To develop cell-based strategies for repairing lung injury, Banerjee et al. [69] differentiated human headStartembryonic stem cellsheadEnd (hES) into lung epithelial lineage-specific cells. According to the authors, the study indicated an increase in progenitor cell numbers in the airway and significantly reduced the collagen content in bleomycin-treated mice, after the transplantation of differentiated hES cells.

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Clinical Trials
Only three headStartclinical trialsheadEnd related to stem cells are considered complete, whereby two are in Phase 1 and one is in Phase 2. All the completed studies were associated with ARDS in the United States (USA) (Table ​(Table1).1). Wilson et al. [70] conducted a Phase 1 trial, where no adverse events were reported in the nine patients evaluated. However, in three patients, serious adverse events were observed weeks after the infusion, but none were MSC-related. The study was considered for an extension trial by Matthay et al. [71]. These researchers carried out a Phase 2 trial in a double-blind study with placebo-control and allogeneic bone marrow-derived-MSCs in a 2 (MSCs):1(Placebo) randomization. The MSC group had significantly higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III) (Table ​(Table1).1). No results were posted in NCT02804945 by the authors.

Final Considerations
Anti-inflammatory therapies for patients with ARDS have been developed using stem cells offering a great promise for managing ARDS [70, 97, 98]. MSCs related cell-therapies demonstrate high efficacy in preclinical data allowing their clinical usage [99]. For COVID-19 research and headStartclinical trialsheadEnd, it is important to consider the blood biomarkers involved in the pathophysiology of the disease which provide therapeutic targets and thus improve the clinical care. Moreover, it is essential to understand the role of endogenous lung progenitor cells during the repair of lung injury and also the mechanism of lung development for developing novel therapeutic strategies [100, 101]. Han et al. [102] mentioned some obstacles in clinical practice that must be considered for COVID-19 as, for example, the low mobilization of transplanted MSCs at the injury site and their low survival rate. The comprehensive interaction between MSCs and the host tissue is a key to the successful therapeutic application whereby experimental studies play a major role in developing lung diseases in clinical translation [37].

Since we know that the mitochondrial disorder caused by the overactivation of Nlrp3 inflammasome is determinant to the pathogenesis of SARS-CoV-2, Nlrp3 inflammasome inhibitors must be taken into account regarding their therapeutic applicability [87–89, 92]. An example for this inhibitory potential is the MCC950 molecule which could affect the binding of SARS-CoV-2 to cells and inhibit the amplification of the intracellular virus, and also the ComC inhibitors that assist in modulating the activity of the innate immune system [93]. Another possible inhibition therapy against SARS-CoV-2 is the use of ACE2 + MSC-derived small extracellular vesicles (sEVs) overexpressed, as suggested by Inal [103].

Regarding the combat against the cytokine storm in the lungs during viral pneumonia, some studies highlighted that the leukemia inhibitor factor (LIF) released by the MSCs may not be expressed enough to supply the damage caused by the disease [104, 105]. As an innovative and technological alternative, there are MSCs with “LIFNano”, nanotechnology that represents a 1000-fold increase in power compared to not using nanotechnology. “LIFNano” acts on damaged tissues and reduces the cytokine storm. Therefore, it represents a therapeutic agent ready to act beneficially against viral pneumonia [106].

Significant advances have been made in three-dimensional (3D) cell culture to develop organoids. These are able to recapitulate the complexity and functionality of different organs. Human lung organoids and bud tip progenitor organoids are composed of cells that are highly similar to the developing human lung. They are ideal for studying developmental biology and tissue engineering. Considering that the cells are specific to the patient’s genetics, the organoids that mimic lung disease may be critical for designing personalized medicine and screening for therapeutic responsiveness [107].

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Conclusion
With the COVID-19 boom, many headStartclinical trialsheadEnd are being carried out using different sources with an emphasis on MSCs. We look forward to the results of the ongoing headStartclinical trialsheadEnd to find a treatment for the disease. Researchers around the world are joining forces to help fight COVID-19. Stem cells used in the current clinical studies are a new therapeutic promise for COVID-19 where pharmacological treatments seem insufficient.
curncman
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Strategies for Scalable Manufacturing and Translation of MSC-Derived Extracellular Vesicles

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Strategies for Scalable Manufacturing and Translation of MSC-Derived Extracellular Vesicles

https://www.sciencedirect.com/science/a ... 6120302798

Abstract
Mesenchymal Stem/Stromal Cells (MSCs) are a well-studied cellular therapy with many clinical trials over the last few decades to treat a range of therapeutic indications. Recently, extracellular vesicles secreted by MSCs (MSC-EVs) have been shown to recapitulate many of the therapeutic effects of the MSCs themselves. While research in MSC-EVs has exploded, it is still early in their development towards a clinical therapy. One of the main challenges in cellular therapy, which will clearly also be a challenge in MSC-EV manufacturing, is developing a scalable, cGMP-compatible manufacturing paradigm. Therefore, the focus of this review is to identify some key MSC-EV manufacturing considerations such as the selection of critical raw materials, manufacturing platforms, and critical quality attribute assays. Addressing these issues early in research and development will accelerate clinical product development, clinical trials, and commercial therapies of MSC-EVs.

7. Conclusions
The imminent therapeutic potential of MSC-EVs is tremendous. As the field starts to translate this regenerative medicine approach to the clinic and for commercial availability, aspects of MSC-EV manufacturing will need to be addressed. Strategic decisions early on in selecting raw materials, the manufacturing platform, and critical quality attributes will together dictate the ease with which scalable manufacturing can be established. Leveraging the knowledge base established by the successes and challenges in manufacturing cells, the MSC-EV field is well-poised for quick translation from research to the clinic.
curncman
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Mesenchymal Stem Cell-Derived Extracellular Vesicles Reduce Disease Severity and Immune Responses in Inflammatory Arthri

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Mesenchymal Stem Cell-Derived Extracellular Vesicles Reduce Disease Severity and Immune Responses in Inflammatory Arthritis

https://www.researchsquare.com/article/rs-70181/v1

Abstract
Background

Novel biological therapies have revolutionised the management of Rheumatoid Arthritis (RA) but no cure currently exists. Mesenchymal stem cells (MSCs) immunomodulate inflammatory responses through paracrine signalling via growth factors, cytokines, chemokines and extracellular vesicles (EVs) in the cell secretome; however, MSCs are still not available in the clinic. We evaluated the therapeutic potential of MSCs-derived EVs in an antigen-induced model of arthritis (AIA).

Methods

EVs isolated from MSCs in normal (21% O2, 5% CO2) or hypoxic (2% O2, 5% CO2) culture or from MSCs pre-conditioned with a pro-inflammatory cytokine cocktail were applied into the AIA model. Disease pathology was assessed 3 days post arthritis induction through histopathological analysis of knee joints. Spleens and lymph nodes were collected and assessed for T cell polarisation within the immune response to AIA. Activated naïve CD4+ T cells from spleens of healthy mice were cultured with EVs or MSCs to assess deactivation capabilities.

Results

All EV treatments significantly reduced knee-joint swelling and histopathological signs of AIA with enhanced responses to normoxic and pro-inflammatory primed EVs. Polarisation of T cells towards CD4+ helper cells expressing IL17a (Th17) was reduced when EV treatments from MSCs cultured in hypoxia or pro-inflammatory priming conditions were applied.

Conclusions

Hypoxically cultured EVs present a priming methodology that is as effective in reducing swelling, IL-17a expression, Th17 polarisation and T cell proliferation as pro-inflammatory priming. EVs present an effective novel technology for cell-free therapeutic translation in treating inflammatory arthritis and autoimmune disorders such as RA.
curncman
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Bioprocess Development for Human Mesenchymal Stem Cell Therapy Products

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Bioprocess Development for Human Mesenchymal Stem Cell Therapy Products

https://www.intechopen.com/books/new-ad ... y-products

Abstract
Mesenchymal stem cells (MSCs) are advanced therapy medicinal products used in cell therapy applications. Several MSC products have already advanced to phase III clinical testing and market approval. The manufacturing of MSCs must comply with good manufacturing practice (GMP) from phase I in Europe and phase II in the US, but there are several unique challenges when cells are the therapeutic product. Any GMP-compliant process for the production of MSCs must include the expansion of cells in vitro to achieve a sufficient therapeutic quantity while maintaining high cell quality and potency. The process must also allow the efficient harvest of anchorage-dependent cells and account for the influence of shear stress and other factors, especially during scale-up. Bioreactors are necessary to produce clinical batches of MSCs, and bioprocess development must therefore consider this specialized environment. For the last 10 years, we have investigated bioprocess development as a means to produce high-quality MSCs. More recently, we have also used bioreactors for the cocultivation of stem cells with other adult cells and for the production of MSC-derived extracellular vesicles. This review discusses the state of the art in bioprocess development for the GMP-compliant manufacture of human MSCs as products for stem cell therapy.

1. Manufacturing cell therapy products

Cell therapy is a growing clinical research and healthcare sector in which living cells are introduced into a patient in an attempt to ameliorate or cure a disease. Stem cell therapy is one of the most promising fields within this sector because the introduced cells have the capacity to differentiate, allowing the repopulation of diseased organs with healthy cells, or to allow even complete organ regeneration. This chapter will focus on one specific type of stem cell (MSCs), which are variously defined as mesenchymal stem cells, mesenchymal stromal cells, or (most recently) medicinal signaling cells [1]. These various definitions reflect the controversial origin and functionality of MSCs and uncertainty about their clinical potential [2, 3]. Following encouraging initial results, the unclear or disappointing outcomes of some MSC clinical trials have clouded the picture [4], but the pioneers of this approach still regard MSCs as a promising therapeutic option [5]. One of the key issues in the deployment of MSCs is ensuring they are safe and effective, which requires a well-characterized manufacturing process.

In order to provide enough MSCs for cell therapy, donor cells must be isolated from tissue and then expanded in vitro to reach a population of 1–9 × 108 cells, which is the typical dose for adult treatment [6]. The success or failure of MSC therapy depends on this in vitro expansion process, which was first studied in detail following the failure of the MSC product Prochymal in phase III trials for graft versus host disease (GvHD) [4], whereas a similar product succeeded in phase II. One reason proposed for the contrasting outcomes of each trial was the substantial differences in the MSC expansion step at the manufacturing scale, highlighting the specialized and complex nature of MSCs [4].

1.1 Definition of MSCs and current approved products
MSCs are classified as advanced therapeutic medicinal products (ATMPs) under regulations in Europe and the US. Many countries follow the regulations laid down by the US Food and Drug Administration (FDA), which defines MSCs as cell therapy products, whereas the European Medicines Agency (EMA) defines MSCs as cell-based medicinal products and distinguishes between somatic cell therapy medicinal products (SCTMPs) and tissue engineered products (TEPs) [7]. This means that clinical studies and drug approval are covered by a specific regulatory framework applied at the national or regional level. Manufacturing must therefore be compliant with good manufacturing practice (GMP) regulations that have been tailored for ATMPs, following strict criteria for product specification and release for clinical use. However, the regulatory framework for MSC manufacturing is confounded by ambiguous product definitions reflecting regional differences in the way the regulations are implemented. For example, the EMA requires GMP compliance and manufacturing authorization for phase I material, whereas the FDA does not apply this requirement until phases II and III, and in Canada, GMP compliance is not strictly required at any phase [8]. Even so, various MSC products have been manufactured under these different regulatory jurisdictions and have proceeded through clinical development, in some cases gaining market authorization from the local regulatory agency [9]. Most of these products are allogenic, which means that MSCs from one or more healthy donors are expanded, processed, and stored and then applied to patients as an off-the-shelf product (Table 1). In 2016, the allogenic MSC product TEMCELL (developed by Mesoblast) was licensed to JCR Pharmaceuticals, which received market authorization in Japan under a fast-track protocol for patients with steroid-refractory acute GvHD. Mesoblast also conducted a phase III trial with this product in the US, involving 60 patients of the same indication, achieving the primary endpoints (NCT02336230). In 2018, ALOFISEL (Takeda Pharma), an expanded allogenic adipose-derived MSC product, was approved by the EMA to treat complex perianal fistula in patients with Crohn’s disease. This was supported by a placebo-controlled trial involving 212 patients [10]. Stempeucel (Stempeutics), an expanded allogenic MSC product, received market authorization from the Drug Controller General of India to treat limb ischemia in patients with Buerger’s disease. However, it is limited to 200 patients on a cost-recovery basis, and a postmarket surveillance study is required. Ninety patients have already received an injection of this MSC product in a phase II trial, achieving a significantly better outcome than standard care [11]. CARTISTEM (Medipost) is an allogenic culture-expanded umbilical cord blood MSC product to treat knee articular cartilage defects in patients with osteoarthritis, grade IV, and following approval for the South Korean market in 2012, its clinical outcomes have remained stable over 7 years of follow-up studies [12]. Several autologous MSC products have also been approved in South Korea, meaning that the MSCs are isolated from the patient’s own tissue and then manipulated/expanded in a patented process and re-injected into the patient 4–6 weeks later. NEURONATA-R (Corestem) and Cellgram-AMI (Pharmicell) are autologous bone marrow-derived MSCs indicated for amyotrophic lateral sclerosis and acute myocardial infarction, respectively. Two other MSC products derived from adipose-tissue have been approved (Anterogen): a mixture of autologous adipose-derived MSCs with other cells for subcutaneous tissue defects (Queencell) and a pure adipose-derived MSC product for Crohn’s fistula treatment (Cupistem) [9]. NEURONATA-R has been designated as an orphan drug by the EMA and FDA.

Product 1 Product 2
Exemplary products ALOFISEL Queencell
Indication Crohn’s disease, perianal fistula Regeneration of subcutaneous tissue
Patients per year 23,000 (in EU)* n.d.
Cell type Allogenic MSCs Autologous, patient-specific MSCs
Cell source Adipose tissue Adipose tissue
Cells per dose 1.2 × 108 MSCs 7 × 107**
Therapeutic relevant cell properties*** Anti-inflammation, immune modulation Regeneration, anti-apoptosis
Manufacturing type Bulk manufacturing Patient-specific batch
Batch size Large (min. 100–1000 doses per batch) Small (1 dose per batch)
Scalability of production Scale up Scale out, several batches in parallel
Product storage Frozen, off-the-shelf No storage
Stability under storage Stable >6 month, frozen Fresh, stable max. 24 hours
Table 1.
Indication and properties of MSC products impact their manufacturing.

*0.003% of all citizens (741 million) in Europe are putative patients.
**Stromal vascular fraction contains MSCs and other cell types such as preadipocytes, endothelial progenitor cells, pericytes, mast cells, and fibroblast.
***Following both products have different critical quality attributes (CQAs) and the manufacturing processes have different critical process parameters (CPPs).
n.d. not determined.

This brief survey of the market shows that the promise of MSC therapy is materializing, with positive efficacy data in controlled clinical trials followed by regulatory approval for a small number of products.

1.2 The therapeutic properties of MSCs
Although MSCs have been used in cell therapy applications for many years, the fundamental biology of these cells and their precise therapeutic properties are not fully understood. MSCs were initially isolated from bone marrow (bm-MSCs) based on their plastic adherence, but today they are usually isolated from adipose tissue (ad-MSCs) or umbilical cord blood (uc-MSCs), which are more accessible [13]. MSCs are also found in various other adult, fetal, and perinatal tissues [14]. Regardless of their origin, MSCs are heterogeneous and polyclonal cells, with at least three subpopulations defined based on morphology. Type I MSCs are spindle-shaped proliferating cells resembling fibroblasts. Type II MSCs are large, flat, epithelial-like cells, which are more senescent than type I cells and feature visible cytoskeletal structures and granules. Finally, type III MSCs are small round cells with a high capacity for self-renewal [15]. The heterogeneity of MSCs can be considered beneficial in that it ensures that some therapeutically active cells are present, but it reduces the maximum potential efficacy because some of the cells are inactive. However, even monoclonal MSCs become heterogeneous during expansion [16].

Despite the heterogeneity described above, the International Society of Cell Therapy has published a set of minimal criteria that must be met before cells can be defined as MSCs. Such cells must (i) show plastic adherence; (ii) be able to differentiate into cartilage, bone, and fat tissue in vitro; and (iii) express the cluster of differentiation (CD) surface markers CD73, CD90, and CD105, but not CD11b, CD14, CD19, CD34, CD45, or HLA-DR [17]. However, this standard set of markers does not distinguish between MSCs and fibroblasts or nonstem mesenchymal cells [18]. Several other markers may be more specific but are only detected in certain MSC isolates or subpopulations. These include stage-specific embryonic antigen-4 (SSEA-4), stem cell antigen-1 (SCA1), nestin, CD44, CD146, CD166, and CD271 [19]. A unique MSC surface marker has yet to be identified.

It is important to note that MSCs cannot be defined merely as a collection of surface markers because this says nothing about their therapeutic effect (Figure 1). Initially, the therapeutic potential of MSCs was believed to reflect their ability to migrate into damaged tissues, differentiate in situ, and replace damaged or dead cells. However, although MSCs can differentiate in vitro, their ability to differentiate in vivo has never been confirmed [20]. Current opinion is that MSCs migrate to injury sites and secrete chemoattractants that recruit tissue-specific stem cells, which in turn generate new tissues or exert positive immunomodulatory effects [1]. The MSC secretome comprises a pool of cytokines, chemokines, growth factors, and extracellular vesicles (carrying proteins, lipids, and various forms of RNA). This secretome differs widely among MSC isolates and subpopulations and can be used to functionally distinguish between several MSC types (e.g., type I, II, and III cells), revealing that the self-renewable type III cells are therapeutically the most effective [16].


Figure 1.
Properties of MSCs and their mode of action. MSCs modulate the host immune systems, e.g., by secreting various trophic factors. Thereby, they reduce inflammation, promote neoangiogenesis, and prevent apoptosis and fibrosis. Further, they stimulate local stem cells to develop new tissue. TSG-6, tumor necrosis factor-inducible gene 6 protein also known as TNF-stimulated gene 6 protein; STC1, stanniocalcin 1; IL-4/6/10, interleukins 4, 6 and 10; CCL20, macrophage inflammatory protein-3; IDO, indoleamine 2,3-dioxygenase; PGE2, prostaglandin E2; VEGF, vascular endothelial growth factor; FGF-2, basic fibroblast growth factor; HGF, hepatocyte growth factor; IGF-1, insulin-like growth factor 1; CXCL12, stromal cell-derived factor 1; MMP1/2/9, matrix metalloproteinase-1/2/9.
The immunomodulatory properties of MSCs and their secretion of anti-inflammatory molecules and extracellular vesicles are an important therapeutic functionality [14]. MSCs are therefore logical candidates for the treatment of immune disorders, including GvHD, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and diabetes [21]. MSCs also secrete peptides and factors that promote the regeneration of damaged tissue by stimulating cell proliferation and migration, promoting angiogenesis, and suppressing apoptosis and fibrosis [14]. The regenerative capacity of MSCs has been used to treat Alzheimer’s disease, bone and cartilage diseases, diabetes, myocardial infarction, and osteoarthritis [22]. Another advantage of MSCs is that they do not form teratomas in vivo, which ensures an outstanding clinical safety profile. Human MSCs achieve senescence without evidence of transformation into tumor cells [23].

1.3 The critical quality attributes of MSCs
The biological complexity and heterogeneity of MSCs hamper the translation of laboratory-scale experiments into industrial processes for cost-effective and reliable manufacturing. This can be addressed by developing MSC manufacturing processes that adhere to quality-by-design (QbD) principles [24]. QbD provides a rational framework and integrates scientific knowledge and risk analysis into process development. It is guided by a thorough understanding of the fundamental biology and engineering principles underlying an MSC product and its production process. QbD begins with a description of the desired product quality characteristics, known as the quality target product profile (QTPP). This is used to identify critical quality attributes (CQAs), which are physical, chemical, and biological attributes that define the quality of the product. The QTPP for MSCs describes properties such as identity, purity, and potency, which will be unique for each MSC product and dependent on the therapeutic indication.

1.3.1 Identity
For MSCs, identity often means the cell phenotype, but as discussed above, there is no agreement on a single definition. Identity is often demonstrated by confirming a typical morphology and/or karyotype [25] and by detecting the presence or absence of surface markers. The minimal criteria for MSCs (see above) have led to a misconception that cells meeting these criteria are equivalent in identity and therapeutic functionality. In polyclonal MSC populations, the presence of multiple cell types can be a clinical benefit as stated above [26], and this should be reflected in the identity attributes.

1.3.2 Potency
The functionality and potency of MSCs are closely linked to their therapeutic efficacy and thus the clinical outcome, but potency is used to demonstrate manufacturing consistency for batch release so a measurable property is required. Viability can fulfill the role of a potency indicator because only living cells can act as a therapeutic entity. Potency can also be measured using in vitro functional assays that determine MSC activity directly or via an indirect metric that correlates to MSC activity in vivo. An assay that measures differentiation potential is only appropriate to describe MSC potency if the therapeutic aim involves engraftment of the cells or tissue formation (notwithstanding the controversy over the assumption that MSCs differentiate in vivo, as discussed above). The FDA mandates that potency is measured using quantitative biological assays [27], so the standard approach is to differentiate MSCs in vitro by cultivating them in differentiation medium and then testing them after 21 days [17]. Staining for differentiation markers is nonquantitative, so alternative methods such as postdifferentiation RNA or protein analysis [28, 29], or the online monitoring of differentiation by Raman spectroscopy [30], are more suitable.

If the therapeutic effect of MSCs is conferred by the secretome, then the differentiation potential may not be the primary determinant of potency. The profile of secreted factors would be a more appropriate measure, and this could be determined by multiplex enzyme-linked immunosorbent assays (ELISAs) or mass spectroscopy [31]. However, a clear link between the secretome profile and in vivo efficacy must be established, so that animal models or cell-based assays can be used to determine the limits of the relevant factors. This is a typical way to move from a complex and highly variable in vivo assay to a multiassay approach combining the quantification of viability, target-specific cytotoxicity or cytokine release, surrogate biomarkers (morphological phenotype or released factors that correlate with function), bioactivity (e.g., presentation of surface markers), cell-based assays, and genomic, transcriptomic, and proteomic profiles [32].

1.3.3 Sterility and purity
Impurities are unwanted components from within the process, whereas contaminants come from outside the process. Impurities during MSC manufacturing include unwanted cell types, particles (e.g., residual microcarriers, or plastics and fibers from manufacturing equipment and materials), or components of culture medium. Contaminants include bacteria, fungi, viruses, endotoxins, and mycoplasma. The heterogeneity of MSCs makes it difficult to detect unwanted cell types. MSC preparations should ideally be pure, but fibroblasts are often present as impurities. Cell-specific sorting based on the marker CD166 (which is expressed at higher levels on MSCs) and CD9 (which is expressed at higher levels on fibroblasts) may help to achieve sufficient purity [33]. In other cases, it may be sufficient if most of the cells in the final product (>98%) fulfill the ISCT minimal criteria based on MSC surface markers. All other impurities and contaminants must be measured and the maximum residual levels must be defined to ensure safety and efficacy. A final sterilization step is not possible when the product is living cells, so the entire MSC production process must be carried out under aseptic conditions.

From the QTPP list, CQAs must be identified, which directly influence the safety and efficacy of the MSC product. This means that a risk assessment is carried out to reduce the QTPP list to the most influential attributes based on impact and certainty. According to ICHQ8, a CQA is “A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.” Therefore, every process parameter “whose variability has an impact on a CQA” is a critical process parameter (CPP) that “should be monitored or controlled to ensure that the process produces the desired quality.” There is no precise delimitation of the degree of impact required to define a CPP, so the broad definition of a CPP is generally divided into parameters that have a substantial impact on the CQAs and those with minimal or zero impact. Each process step has multiple CPPs. For example, during the in vitro expansion step, CPPs can be directly associated with the MSCs (e.g., cell density and cell age) or raw material attributes (e.g., medium, serum, and growth factors) or operational features of the culture vessel/bioreactor system (e.g., pH, temperature, dissolved oxygen, and agitation). The effect of each CPP on the CQAs must be quantified in a design space. With an appropriate control strategy, the CPPs are kept in their normal operational range, which ensures the production of high-quality MSCs that meet all the required CQAs. Based on the heterogeneity and the complexity of MSCs, each MSC product can have unique CQAs and the corresponding CPPs must be identified case by case.

2. Expansion of human MSCs in vitro

Therapeutic applications of MSCs require at least 1 × 108 cells per dose, which is many more than can be isolated by tissue aspiration. All MSC production processes must therefore include an in vitro expansion. Having generated or isolated the starting cell population, in vitro expansion is followed by harvest, concentration, purification, formulation, fill and finish, storage, and shipping. The manufacturing steps of MSCs are therefore similar to the production of recombinant proteins, but MSCs are more challenging due to the variability of the starting material, the complexity of living cells as a product, an incomplete understanding of their mechanism of action, and the inherent difficulties encountered during product characterization.

2.1 CPPs that affect MSC manufacturing
The properties of MSCs are strongly influenced by the environment because MSCs in nature interact with surrounding cells and tissues, with the extracellular matrix and with various bioactive molecules. Even in an artificial environment like a bioreactor or T-flask, MSCs are very sensitive to their environment, and the most influential factors give rise to CPPs. By identifying CPPs that affect MSC quality, the process can be designed to favor the recovery of MSCs with specific phenotypes of interest, in this case those with the greatest therapeutic efficacy [34, 35]. The CPPs affecting MSC quality are discussed in more detail below.

2.1.1 Cell density and age
During MSC isolation, the seeding density is important because all sources contain different quantities of MSCs. For example, only 1 in 100,000 bone marrow cells is an MSC, whereas in adipose tissue, the ratio is nearer to 1 in 100 [36]. If plastic adherence is selected as a strategy for MSC isolation, the number of adherent cells therefore differs according to the source if a similar number of tissue cells are seeded. Standardization during this step can be achieved by isolating MSCs using a strategy of surface marker sorting, allowing a defined number of cells to be seeded into the culture vessel. The seeding density selected for the in vitro expansion step is a CPP. MSCs can be seeded at a very low density (50–100 cells per cm2) and will proliferate until they achieve confluence. This corresponds to a high expansion factor, but the process takes a long time and requires more rounds of cell division for each seeded cell, so the cells experience significant aging [37]. The aging of MSCs during expansion is a problem, because older cells lose competence to behave as stem cells and have a tendency to enter senescence or even to undergo transformation. The manufacturing of Prochymal provided a clear example of this issue: 10,000 or more doses were manufactured from one donor, and the corresponding expansion stress led to replicative senescence, in which the cells retained a typical MSC surface marker profile but lost functionality [4]. Aging MSCs are more likely to activate a senescence-associated secretory phenotype and produce pro-inflammatory cytokines such as IL-1, IL-6, and IL-8, which inhibit the regenerative process. The duration of in vitro expansion must be considered not only because of senescence, but also due to the phenomenon of clonal impoverishment. MSCs are polyclonal, but prolonged expansion favors the growth of specific cell types or clones. Depending on the expansion time and expansion factor, the cell mixtures may completely differ in phenotype and also in potency. Therefore, although a high expansion factor in a short process time is desirable to achieve high product yields, in vitro expansion should never change the properties of MSCs to the extent that it compromises their functionality and potency.

2.1.2 Culture medium
Several basal media have been shown to influence MSC expansion and potency, including Dulbecco’s modified Eagle’s medium (DMEM), Iscove’s modified Dulbecco’s medium (IMDM), and MEM alpha (αMEM) [37]. One of the key components of these media is glucose, which is the main carbon source for MSCs. Glucose may be provided at physiological concentrations (1 g/L) or higher (up to 4.5 g/L), the latter variously described as having a negative effect on MSC proliferation and growth factor secretion [38] or no effect at all [39]. Glutamine as a second carbon source is present at concentrations of 2–4 mM and appears essential for MSC growth [40], but its impact on MSC properties is complex, with contradictory results [41, 42, 43]. Glutamine is unstable at 37°C and spontaneously degrades to form ammonia. GlutaMAX (dipeptide Ala-Gln) is recommended instead of glutamine to promote MSC expansion [44]. Lactate and ammonia are the most abundant waste products formed by MSCs, and both therefore have the potential to inhibit growth. It therefore follows that glucose, glutamine, lactate, and ammonia levels should be considered as CPPs for the production of MSCs. Several other amino acids may also be relevant, given that the amino acid metabolism of MSCs differs from that of commercial cell lines such as Chinese hamster ovary (CHO) cells [42].

Basal media formulations must be supplemented to achieve MSC expansion. The most important supplement is fetal calf serum (FCS), which is added to a final concentration of 5–20%. FCS strongly influences MSC growth and phenotype, but the specific effectors are unknown because the composition of FCS is variable and lot-dependent [45]. The use of FCS for the manufacture of clinical MSC products is discouraged nowadays, in line with the drive to eliminate all raw materials of animal origin. The complex, uncertain, and variable composition of FCS also makes it difficult to validate for GMP-compliant processes. Finally, the manufacturing process must accommodate steps to eliminate FCS from the final product to avoid potential immunogenicity and allergenicity [46]. FCS can be replaced with human serum and its derivatives, such as human platelet lysate, which promotes MSC growth [47]. However, the same lot-dependent quality issues described above for FCS also apply to human serum [48]. The most acceptable alternative is serum-free or preferably chemically-defined medium, the latter not only serum-free but also lacking any hydrolysates or supplements of unknown composition. MSCs grow well in several commercial serum-free media, including BD Mosaic MSC Serum-free (BD Biosciences), RoosterNourish (Rooster Bio), Mesencult-XF (Stemcell Technologies), StemPro MSC SFM Xeno-Free (Invitrogen), TheraPEAK MSCGM-CD (Lonza), and PPRF-msc6, STK1 and STK2 (Abion) [49]. Growth in chemically-defined medium has also been demonstrated [50]. However, although MSCs showed excellent growth in these serum-free media, they reached senescence earlier, and there were changes in morphology, surface marker profiles, and potency [51]. This does not mean that serum-free and chemically-defined media should be avoided‑it is still better to use these media for MSC expansion in order to meet GMP requirements‑but further investigations are required to optimize the media composition. The development of serum-free media is mainly driven by companies, which tend not to disclose the precise composition, making it difficult for other researchers to build on the results. In serum-free and defined media, supplemental growth factors such as FGF2 and PDGF are needed to stimulate MSC proliferation, but they also influence MSC potency [18]. Accordingly, chemically-defined media would be preferable for the in vitro expansion of MSCs, but growth factor concentrations are important CPPs that affect MSC identity and potency and must be carefully controlled.

2.1.3 Conditions in the culture vessel
MSCs are aerobic cells and any culture vessel must therefore ensure an adequate supply of oxygen. However, the oxygen saturation in standard T-flasks (21% O2) is far removed from nature (5–7% O2) [34]. MSCs therefore tend to be oversaturated with oxygen, which can increase the concentration of damaging reactive oxygen species (ROS). Several studies have confirmed that hypoxia enhances MSC proliferation, stabilizes their cell fate, and prevents apoptosis by reducing the levels of caspase-3 [52]. However, rather than imposing hypoxia by preconditioning the cells, it may be better to impose hypoxia during the entire expansion phase, because this mimics their natural niche [53].

In addition to oxygen saturation, temperature and pH are CPPs in every process and can be monitored and controlled very easily. Typically, in vitro expansion is carried out at 37°C and neutral pH (7.2–7.4). Expansion at lower temperatures can be advantageous under certain circumstances because this reduces stress (ROS production and frequency of apoptosis) and may yield more potent MSCs. Although the expansion of MSCs has been achieved in the pH range 7.5–8.3 [54], it is unclear how significant variations in pH influence MSC metabolism and whether this affects the secretome. The optimal temperature and pH must be evaluated for each MSC product.

Other CPPs include the parameters grouped under the term hydrodynamics, referring to the potential impact of aeration and agitation. Aeration is required to supply oxygen to the MSCs, but as well as affecting the oxygen saturation, it also generates forces that cause physical stress. In T-flasks, aeration is achieved by the diffusion of oxygen through the surface of the medium, whereas bioreactors must be actively aerated by, e.g., bubbling gas into the liquid. The bursting gas bubbles (cavitation) generate strong forces that can damage cells, although the stress can be reduced by controlling the bubble size [55]. Agitation in bioreactors is generally achieved with impellers, which help to disperse gas (and therefore contribute to aeration) but also maintain a homogenous suspension of cells and nutrients. The creation of a homogenous environment is advantageous because it avoids gradients of pH, nutrients, or waste products, whose effect on MSCs is unpredictable. Homogenization can also be achieved using pumps or is facilitated by air bubbles. Agitation always generates shear forces, so it is necessary to balance the homogeneity of the cultivation system and the impact of the hydrodynamic forces on the MSCs. Although excessive shear stress is detrimental, hydrodynamic forces can also stimulate MSC growth and increase potency [43]. For these reasons, the mode and rate of aeration and the method and intensity of agitation are CPPs that must be carefully optimized for each process.

2.1.4 Growth surface, cell harvest, and storage
MSCs are anchorage-dependent cells, so the properties of the growth surface also have a significant impact on the process and must be investigated and selected carefully. However, unlike the parameters discussed above, the growth surface does not have to be monitored or controlled during MSC production, so it falls outside the technical definition of a CPP. The expression of certain surface markers by MSCs reflects the stiffness of the growth surface, so it is clear that the surface affects the phenotype [56]. As stated above, the ability to adhere to plastic surfaces is one of the minimal criteria that define MSCs, and tissue-culture plastic is therefore the most commonly-used growth surface. Although all commercial tissue-culture plasticware has a polypropylene base, the surface is often treated differently, and this changes the behavior and properties of the adherent MSCs [37]. MSCs further grow on other surface materials, e.g., glass [57] or dextran [58]. When MSCs are cultivated in serum-free medium, cell growth often requires that the surface is coated with further adhesion-promoting factors, such as fibronectin, vitronectin, or the peptide RGD.

Given that MSCs are anchorage-dependent cells, the harvesting of cells at the end of the in vitro expansion step requires an efficient cell detachment method that ideally does not affect functionality or potency. In the laboratory, MSCs can be detached from T-flasks by adding trypsin or other proteases, but this nonspecific proteolysis can affect cell viability and eliminate some MSC surface markers [59]. Proteolytic cleavage is incompatible with the larger-scale processes in bioreactors because longer incubation times are required for the enzymes to work, and even then, the efficiency of cell recovery is low [60]. More importantly, any negative effects of the enzymatic treatment on cell viability and potency are amplified by the longer exposure time, which can inhibit MSC differentiation [61]. These issues can be addressed by adjusting the hydrodynamic conditions to favor cell detachment after limited enzymatic treatment [62]. Alternatively, enzymatic treatment can be circumvented completely by promoting cell detachment using dissolvable growth surfaces [63] or thermosensitive surfaces that release cells following a temperature shift [64, 65]. However, unlike enzymatic treatments, these novel surfaces do not break direct cell-cell bonds and may be unsuitable if single cell is required. The formation of aggregates can be minimized by carefully monitoring the cell density and selecting a harvest point that favors the recovery of single cell, but this must be balanced against the efficiency of expansion given the need to harvest at lower cell densities. The so-called harvest problem, balancing the efficient release of cells against the recovery of cells with desirable properties, has yet to be solved. This highlights the importance of well-defined CPPs at the harvesting stage.

All the approved allogenic MSC products described earlier are cryopreserved, allowing them to be offered as off-the-shelf products that can be stored until quality control and batch release are completed. The use of cryopreserved allogeneic MSCs is the only feasible therapeutic strategy for acute tissue injury syndromes such as stroke, sepsis, or myocardial infarction, because the patient is likely to die before sufficient quantities of autologous MSCs could be prepared. However, cryopreservation and thawing have a massive impact on the potency of MSCs [66]. Indeed, even without optimization, fresh MSCs are much more potent than frozen ones [35]. A rule of thumb is to freeze the cells slowly (e.g., 1°C/min) but to thaw them quickly (e.g., direct transfer from storage to a 37°C water bath). The impact of multiple freeze-thaw cycles must be evaluated carefully [67]. The composition of the freezing medium is also important because it often contains dimethyl sulfoxide (DMSO) and FCS as cryoprotectants, the first being cytotoxic and the second undesirable for the reasons already discussed above. Nontoxic alternatives lacking DMSO and FCS have been tested and may be more compatible with MSCs intended for clinical applications [68, 69, 70].

CONCLUSIONS
MSCs are potent therapeutic agents, but their complexity and environmental sensitivity make the GMP-compliant manufacturing of MSC products extremely challenging. Given the range of tissue sources, isolation procedures, and expansion protocols, it is unclear whether MSC products are similar enough across manufacturing sites and whether results can be considered comparable even within the same study. Moreover, the incomplete definition of MSCs makes it difficult to develop objective release criteria. These issues strongly argue for the harmonization and standardization of MSC manufacturing processes, release criteria, and potency assays. The regulatory standards for MSCs are still evolving, and different standards apply in different jurisdictions. MSCs are living cells and cannot be held to the same standards as chemical entities or biopharmaceuticals, both of which can be tested against rigorous and objective quality criteria. The regulations for MSCs should be more flexible, acknowledging that each MSC product is developed for a specific indication, and unique platform technologies, CQAs, and CPPs may therefore be necessary for each manufacturing process. One of the most important platform technologies is the use of bioreactors for cell expansion, because this is the only current strategy that can bring MSC therapy into routine practice. MSCs can also be used as production aids for other products, including beta cells for drug screening or diabetes therapy, and novel biological agents such as extracellular vesicles. In the future, they could even be used for commodity products such as artificial meat. But in all these applications, a robust and scalable manufacturing process will be necessary.
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JADICELL -Mesenchymal Stem Cells: Discuss Mesenchymal Stem Cells to Treat COVID 19 Cytokine Storm

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Discuss Mesenchymal Stem Cells to Treat COVID 19 Cytokine Storm

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Human mesenchymal stem cells incubated with neurogenic differentiation medium
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Issues when using Human Umbilical Cord Mesenchymal Stem Cells (hUC MSCs) - CytoSMART Academy

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Mesenchymal stem cells or stromal cells? - Pr. Pr Karin Scharffetter - Kochanek

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Mesenchymal stem cells or stromal cells? - Pr. Pr Karin Scharffetter - Kochanek


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Human Mesenchymal Stem Cell interacting with 3D hydrogel

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Human Mesenchymal Stem Cell interacting with 3D hydrogel




Turning MSC+ Mesenchymal Stem cells into Functional Neurons

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Re: JADICELL -New Stem Cell Therapy for COVID-19 Finds Success in Clinical Trial at Baptist Health

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New Stem Cell Therapy for COVID-19 Finds Success in Clinical Trial at Baptist Health
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Basic principles of mesenchymal stem cell biology and their potential for clinical applications

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Basic principles of mesenchymal stem cell biology and their potential for clinical applications


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