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

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JADICELL -Effects of mesenchymal stromal cell-conditioned media on measures of lung structure and function: a systematic

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Effects of mesenchymal stromal cell-conditioned media on measures of lung structure and function: a systematic review and meta-analysis of preclinical studies


https://link.springer.com/article/10.11 ... 20-01900-7
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JADICELL -Stem Cells May Help COVID-19 and ARDS Patients Breathe Easier

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Stem Cells May Help COVID-19 and ARDS Patients Breathe Easier

https://www.biospace.com/article/stem-c ... he-easier/

Published: Sep 15, 2020 By Chelsea Weidman Burke

“ARDS makes you feel like you can’t breathe, like you’re suffocating,” said Eileen Rubin, J.D., ARDS survivor and Founder of the ARDS Foundation.

Acute respiratory distress syndrome (ARDS) is as scary as it sounds. A person is usually sick with something else, such as the flu, COVID-19, or sepsis (a serious bloodstream bacterial infection), before they develop ARDS. Suddenly, the person has trouble breathing, is short of breath, and feels like they are suffocating. ARDS patients quickly go into respiratory distress and usually need to be put on a ventilator (and are typically put into a medically induced coma) to get them the oxygen they so desperately need.

“Within about two days in the hospital, I went into respiratory arrest and was diagnosed with ARDS at age 33,” Rubin explained. “I spent nine weeks in the hospital, eight weeks on a ventilator, and four weeks in a medically induced coma.”

Despite the seriousness of ARDS, Rubin wants those affected by the disease and their families to know there is hope. Over 50% of the almost 200,000 Americans diagnosed with ARDS each year recover and it is not a terminal illness.

“ARDS patients are given the grim statistics about what is going to happen to them and how dire it is,” she added. “Where there is life, there is hope – families should talk to their ARDS loved one if they’re in a coma, tell them the reasons they need to have hope and focus on the things they need to survive for.”

This year, more people will be diagnosed with ARDS due to COVID-19. ARDS tends to develop in severely ill COVID-19 patients and is a common cause of death in these critical patients.

Rubin told BioSpace how her ARDS experience prompted her to help others by creating the ARDS Foundation. We also spoke to Gil Van Bokkelen, Ph.D., CEO of Athersys, a company developing stem cell therapy to treat ARDS, which is currently being tested in COVID-19 patients who develop ARDS.

Eileen’s story: “I can’t breathe. I think I’m dying.”

It all started with lower back pain – not something you think would land you in the hospital on a ventilator, fighting for your life days later.

“I was suffering from excruciating lower back pain for eight days before going to my doctor,” Rubin explained. “They said I likely pulled a muscle, prescribed me a muscle relaxant, and sent me home.”

A week later, she still felt horrible and was having difficulty breathing. She saw another doctor, who basically said the same thing and didn’t order any tests, sending her home with the same muscle relaxer.

The next morning, she awoke around 5:00 a.m. with labored breathing and difficulty walking. After calling her doctor, they said they wouldn’t see her again because they had just seen her yesterday. Frustrated and scared, she found another doctor who saw her later that afternoon. By then, her blood pressure was dangerously low (70/50), she had blood in her urine and she became delirious. This third doctor finally ordered bloodwork and a chest x-ray but sent her home to await the results.

She awoke very early the next morning to a phone call from the doctor telling her to go to the emergency room immediately – her white blood cell count was 3.5 times higher than normal. Once in the emergency room, she saw a pulmonologist who said she would need to be ventilated if her breathing got any worse. That night, her kidneys failed. Luckily, she was stabilized, but during her second day in the hospital, she became extremely short of breath.

“I said to my mother, ‘I can’t breathe. I think I’m dying.’ And my mother ran out of the room,” Rubin recounted. “My mother rushed to find my internist and repeated what I had said. My internist said, ‘She’s okay, I just saw her. She’s just anxious.’ My mother replied, ‘Listen, she just said this, and I need you to come see her now.’ So, the doctor came in and saw me.”

Upon realizing how badly Rubin was doing, her doctor cleared the room, called a code and declared that she was in respiratory arrest. Almost three hours later, her family was let back into her room, only to find her ventilated in a medically induced coma.

Unfortunately, this pain denial isn’t uncommon – pain that women experience is far too often downplayed, not taken seriously, or outright dismissed in healthcare.

“A woman in her 30s says she has pain in her chest and is having difficulty breathing is seen totally differently than a man with the same symptoms,” Rubin noted. “My doctors didn’t even consider doing an EKG.”

After receiving many units of blood, having her lungs collapse multiple times, developing some hospital-acquired infections and having five chest tubes placed, she was sent home to slowly recover after nine weeks in the hospital. Read her entire battle with ARDS, “From Trial Attorney to Life Support in Only Days…,” on the ARDS Foundation website.

ARDS Foundation

A few years after recovering from her battle with ARDS, Rubin wanted to help other ARDS patients and their families, providing the information and support that she and her family didn’t have.

“When my sister went on the internet, all she got were medical articles filled with jargon and autopsy photos,” Rubin commented. “There was nothing positive written about ARDS, nothing that offered any support.”

Rubin wanted to change that, so she created the ARDS Foundation in 2000. The foundation initially started to create a simple, easy to understand brochure for families explaining what ARDS is. Today, it is a nonprofit organization offering support, information, and awareness of ARDS to patients and families.

“After ARDS, a lot of people become less outgoing, more reserved,” Rubin noted. “They don’t feel like doing certain things and their personality changes – they may suffer from anxiety, depression, or PTSD because their life is completely altered.”

The foundation is also facilitating medical research to improve ARDS care and treatment.

“My ARDS was treated much like it is today, with supportive therapy and ventilation – there is no specific treatment for ARDS,” Rubin explained. “My doctors were just trying to put out all the fires that were going on while I was critically ill.”

A stem cell therapy for ARDS

One company working towards an ARDS treatment is Athersys, a biotech company focusing on regenerative medicine therapies for diseases with significant unmet need. Their product, called MultiStem®, is a certain type of off-the-shelf human stem cell being studied to treat a wide array of conditions, including neurological, cardiovascular, inflammatory, and immune diseases.

To make this therapy, stem cells are isolated from the bone marrow of healthy donors and separated to collect a certain population of cells called multipotent adult progenitor cells (MAPC). These specific stem cells are expanded in the lab to become MultiStem; they can be frozen for extended periods of time, ready for use when a patient needs them.

“These cells have a robust and highly distinctive expansion potential – material from a single donor can be used to produce millions of doses, which is well beyond the limits of other donor-derived cell types,” explained Van Bokkelen.

MultiStem cells don’t express molecules that would elicit a rejection response, meaning they don’t require donor-recipient matching or immune suppression when being given to the patient. “The cells can be used like a universal donor Type O blood product,” Van Bokkelen added.

Because of the time sensitive nature of the conditions MultiStem is being used to treat (ARDS, stroke, trauma), timing is everything; being able to simply thaw ready-to-use cells and administer them to the recipient rapidly is key. Once the cells are delivered into the patient, they express a range of proteins and immune factors, giving the cells a unique ‘drug-like profile.’

“We’re administering living cells that are dynamically responsive to the signals and cues produced by the human body, unlike traditional pharmaceuticals or biologics that are designed to do one very specific thing,” said Van Bokkelen. “MultiStem is a living multifactor delivery system – the cells home to sites of tissue damage and inflammation where they perform a whole series of actions.”

When a virus like COVID-19 or another pathogen enters the body, the immune system becomes activated to destroy the pathogen. Sometimes, a hyperactive, over inflammatory state is triggered, which can actually be counterproductive and harmful. In fact, this “cytokine storm” is thought to cause ARDS in severe COVID-19 patients, resulting in the need for ventilation and frequently leading to death among seriously and critically ill individuals.

“If we administer MultiStem cells to patients in this hyperinflammatory state, the cells will home to the spleen, the warehouse of activated immune cells, and calm everything down, restoring immunological homeostasis,” Van Bokkelen explained. “MultiStem cells don’t just regulate one type of cell, they regulate a whole series of pathways – that is what makes them so powerful.”

Once the overactive immune response has been reigned in, the body is able to recover and heal faster, rather than spiraling out of control.

You might be thinking, “If we have these stem cells inside us already, why wouldn’t they do the same thing and tamp down the overactive immune response in the first place?” While a person in the throws of a hyperactive immune response may have some of these specific stem cells (usually there is a very small amount in the bone marrow), they are slow to mobilize and there may not be enough to balance out the ‘storm’ of activated immune cells.

“If someone sustains a serious injury and they’re losing lots of blood, we give those patients a blood transfusion,” Van Bokkelen posed. “It’s not that the body can’t make red blood cells, it’s just that it can’t do it fast enough to deal with the rapid blood loss. Similarly, we can administer MultiStem to a patient much faster than the body would be able to respond on its own, helping to get things back to where we want them to be.”

A similar situation happens during a hyperactive immune response – administering MultiStem to provide the body with more calming stem cells helps balance the immune response quickly to avoid damage to the patient.

Another bonus of these cells is that they have a finite half-life in the body; unlike a bone marrow transplant that replaces the bone marrow permanently, MultiStem cells are cleared over time just like other normal cells in the body.

MultiStem cells to treat COVID-19-induced ARDS

When COVID-19 appeared, the Athersys team thought MultiStem may be helpful for ARDS in COVID-19 patients because it had already been tested in ARDS animal models and clinical studies. Previously, MultiStem, delivered either intravenously or directly to the lungs (endobronchially), effectively treated ARDS in sheep alone and in conjunction with extracorporeal membrane oxygen (ECMO).

Athersys concluded a randomized, double-blind, placebo-controlled Phase I/II study (MUST-ARDS) last year in 36 ARDS patients. Patients treated with MultiStem had:

More ventilator-free days (12.9 days vs. 9.2 days for the placebo-treated group)
More ICU-free days (10.3 days vs. 8.1 days in the placebo group)
A lower mortality rate (25 percent vs. 40 percent in the placebo group)
Improved quality of life 1-year after treatment compared to the placebo group, with even larger clinical benefits among the more seriously ill
Overall, the cells were well-tolerated with no serious adverse reactions within 24 hours of administration.

“We saw a dramatic difference one year after patients received a single dose of MultiStem,” Van Bokkelen said. “We were really helping patients get on the path to recovery and get back to where they wanted to be in terms of functional independence and quality of life.”

The company currently has two ongoing studies of MultiStem in ARDS patients: ONE-BRIDGE, a Phase II study in non-infection induced (pneumonitis) ARDS patients; and MACoVIA, a Fast Track designated Phase 2/3 study in COVID-19 induced ARDS patients.

ONE-BRIDGE, sponsored by HEALIOS K.K., is a randomized study aiming to enroll 35 adult participants to assess MultiStem’s safety and effects on ventilator-free days and various biomarkers. Enrollment is expected to be completed by the end of 2020.

MACoVIA is a randomized, placebo-controlled study designed to enroll up to approximately 400 adult participants to assess MultiStem’s safety and tolerability in COVID-19 ARDS patients, as well as evaluate its effect on ventilator-free days and all-cause mortality. “We worked with the FDA to get study approval in an accelerated timeframe of a few months – we started enrolling patients in early May,” added Van Bokkelen. “We’re hoping to complete the study sometime next year.”

“We welcome the progress being made by Athersys to find a solution to the huge unmet need of ARDS treatment,” Rubin commented. “We hope that their Phase 3 trials are completely successful because this treatment is much needed. We support all companies engaging in research on treatment options for ARDS.”
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JADICELL Challenges with implementing mesenchymal stem cells into practice

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Challenges with implementing mesenchymal stem cells into practice


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JADICELL - NFL Alumni’s Work in Regenerative Medicine and Cell Therapies - September 16, 2020

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Panel 11 - NFL Alumni’s Work in Regenerative Medicine and Cell Therapies - September 16, 2020
Watch from 26th minute
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Re: JADICELL -Panel - 10 Roundtable Discussion: Policy Actions to Advance Regenerative Medicine and Cell Therapies

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Panel - 10 Roundtable Discussion: Policy Actions to Advance Regenerative Medicine and Cell Therapies
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Re: JADICELL -Mesenchymal Stem Cells: A New Piece in the Puzzle of COVID-19 Treatment

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Tissues | Mesenchyme & Loose Connective Tissues

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JADICELL The quality evaluation system establishment of mesenchymal stromal cells for cell-based therapy products

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The quality evaluation system establishment of mesenchymal stromal cells for cell-based therapy products

https://stemcellres.biomedcentral.com/a ... 20-01696-6

Discussion
The quality control of CTPs is at least performed in three respects which include donor screening and starting material selection, in-process testing of cell products in GMP manufacturing, and release testing of the final product before clinic use [28]. In this study, we established a quality evaluation system to ensure the safety of therapeutic HUCMSCs as a CTP in clinic. We integrated various aspects regarding the characteristics and efficacy of HUCMSCs into a practical system of safety evaluation and quality control, which included GMP environmental monitoring program, quality control of critical raw materials and reagents, donor screening criteria and method, microbial contamination, cell viability, apoptosis, proliferation, cell cycle and growth curve, expressions of surface markers, differentiation potentials, karyotype analysis and tumorigenicity, and immune regulation capability and release assays.

The HUCMSC manufacturing facility and environment must meet the requirements of GMP for pharmaceutical manufacturers to minimize the particle and microorganisms in the final cell therapy product as far as possible [16]. It is relatively easy to design and construct a GMP-grade cell facility; the difficulty lies in implementing an effective environmental monitoring and maintenance program to smoothly run the cell bank. Environmental monitoring programs implemented in our center include physical environment, microbiological, and personnel controls. The environmental parameters of GMP laboratory such as lighting, temperature, humidity, air pressure, airflow volume, and velocity must be strictly controlled to ensure all parameters reach the GMP standards before processing. Acceptance criteria for temperature and relative humidity are 22 ± 2 °C and 30~50%, respectively. Environmental microbiological monitoring in the laboratory includes the detection of air and surface (laminar flow cabinet). The air plate sedimentation method was used for microbiological monitoring, and microbial contamination levels were expressed by counting cfu and particle monitoring; the alert and action limits for GMP laboratory and laminar flow cabinet are 4 cfu/30 min/dish (150 cfu/m3) and 0.2 cfu/30 min/dish (5 cfu/m3), respectively. Laboratory workers are the main source of microorganisms in the cell facility, and they can significantly affect the quality of product processing environment. To ensure that all personnel (even those who are in charge of cleaning and maintenance) receive appropriate training before entering the GMP lab, the training includes sterile operation, personal hygiene, laboratory contamination, and GMP-related knowledge. In addition to the relevant training, regular personal sampling monitoring was conducted too, such as gloves and work clothes before and after the operation and cultured with agar plates. After incubation, the results are expressed by counting cfu; the alert and action limits are 5 cfu/cm2 according to “Hygienic standard for disinfection in hospitals GB15982-2012” in China.

MSC donors must undergo strict eligibility determinations to screen healthy donors without transmit infectious diseases, malignant tumors, mental illness, and refractory chronic diseases. In our previous study, we found that even if HUCMSCs were derived from HBV women, the current cell-based testing assays failed to detect HBV in these cells, indicating that cell-level virus detection is not reliable in cell-based therapy [19]. Thus, we put forward that MSC donors should undergo other communicable disease tests at 3 months after the first serological communicable disease screening to exclude the potential window period of these viral infections in donors. In our practice, donors undergo communicable disease tests twice including HBV, HCV, HIV I and II, syphilis, CMV, and EBV, and in all tests, diseases must be negative in eligible donors. If the second serological screening is not available from the donor 3 months later, or any of the tested infectious diseases is positive in the second serological screening, the cultured cells from this donor are judged to be unqualified for clinic use based on the agreements in prior written consent, and all the expanded cells will be discarded as medical waste, even the cells have passed the systematic quality evaluation.

MSCs are broadly used in a variety of diseases due to their diverse physiological features such as preferential migration to damaged tissues, differentiation potentials of various cell types, and secreting tissue-renewing anti-inflammatory factors [29,30,31,32]. The parameters of HUCMSCs’ quality include identity, purity, viability, safety, and potency. Of which, the most challenging parameter is the potency test for MSC-based products because it should represent one or more of the cells’ relevant functions in vivo [28, 33]. Therefore, the potency assay of HUCMSCs should include not solely cellular phenotype assay, but also functionality relevant assay. In our quality system of HUCMSCs, we test the surface markers of HUCMSCs (positive CD73, CD105, and CD90; negative CD19, CD45, CD11b, CD34, and HLA-DR), viability, apoptosis, proliferation rate, growth curve, tumorigenicity, and karyotype analysis to assay identity, purity, viability, and safety of cells. In viability and growth assays, multiple methods are performed including trypan blue exclusion, apoptosis, EDU immunostaining, and cell cycle analysis. In addition, in these assays, a tumor cell line was used to act as a positive control because of the relatively stable characteristics of the tumor cell line. It also could be used as a reference standard to compare the viability and growth of different batches of HUCMSCs derived from different donors. For potency assay, we focused on the differentiation potentials into osteoblasts, adipocytes, and chondroblasts, and general immunomodulatory role of HUCMSCs. In differentiation assay, we established positive controls such as mouse adipose tissue section staining for adipocyte differentiation, mouse bone section staining for osteocyte differentiation, and mouse chondrocyte bone section staining for chondrocyte differentiation to evaluate whether the differentiation experiments are successful and the sufficiently potent or sub-sufficiently potent batches.

MSCs have been explored for a wide range of hyper-activated immune disorders such as transplant rejection, GVHD, and autoimmune diseases, due to the immunomodulatory activity of MSCs [34, 35]. The mechanism by which MSCs play the general immunomodulatory effects involves the orchestration of immune tolerance, then regulating the functions of regulatory B and T cells and innate suppressor cells as well [36]. In this study, we assayed T subpopulation of PBMCs by co-culturing with HUCMSCs to evaluate the immunomodulatory effects of HUCMSCs. HUCMSCs remarkably inhibited the proliferation of CFSE-labeled PBMCs by co-culturing and suppressed the activation and differentiations of CD4+ T cells into Th1 and Th17 subpopulations. In addition, HUCMSCs exert the maturation of Treg subpopulation in PBMCs induced by IL-2. Overall, MSCs could skew the inflammatory niche into an anti-inflammatory one, via direct and indirect immunoregulatory activities of Tregs and monocytes [37, 38].

Before being released for clinical application, each HUCMSC batch must undergo release testing assay. Because the HUCMSCs have undergone a systemic in-processing quality assay and were judged to be a qualified cell product, the release assay should be relatively simple and be finished quickly. In our system, the release assay includes bacterial, fungi, endotoxin, mycoplasma, cell amount, and viability as the final safety assurance for recipients. The qualified HUCMSCs adjudged based on the results after the in-process and release assessments were tested for treating a variety of diseases including premature ovarian failure (POF), coronary artery disease (CAD), diabetic erectile dysfunction, type 1 diabetes mellitus, nasal septum injury, and liver failure in our hospital. In total, 225 patients received HUCMSC treatment, only 5 cases had a transient slight fever, one case had a headache, and 2 cases had nausea within 2 days after HUCMSC transplant; no other adverse outcomes were observed during the 1-year follow-up period, indicating our established systemic quality control and assessment were effective to ensure the quality and safety of HUCMSCs as cell therapy products in clinical application.

As outlined earlier in our study, our system only established a minimum set of standards for HUCMSCs, and there were some shortcomings due to the limited understanding of the MSC mechanism of action in stem cell therapy. Each MSC product has unique biological characteristics due to tissue origin, donor conditions (age, gender, and individual heritability), passage number, cell preparation, and pre-modulation before application. Thus, each MSC product requires definitive criteria in every potent assay such as differentiation potential and immune regulation according to its own characteristics. In addition, although HUCMSCs have been successfully tested for various indications in the pre-clinical phase or clinical trials, its mechanism differs among indications. For example, in the field of immunotherapy, the immunomodulatory actions of HUCMSCs are considered to exert its therapeutic effects, but not the differentiation potential. Thus, some potent assays regarding immune regulations are preferred above other assays such as adipogenic, chondrogenic, and osteogenic differentiation potentials. Therefore, it needs to develop specific potent assays in line with a certain indication with a further understanding of MSCs and diseases.

Conclusion
In this study, we establish a systemic quality control and potent assays to guarantee the safety and effectiveness of HUCMSCs based on a minimum set of standards in MSC-based product. The qualified HUCMSCs were tested for various indications, and no severe adverse reaction was observed during the 1-year follow-up period, indicating our system is valid for quality control and assessment of HUCMSCs as a cell-based product.
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JADICELL -Cryo Cell

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Cryo-Cell

Umbilical cord tissue is able to be collected at the same time as umbilical cord blood and contains another type of stem cell called mesenchymal stem cells (MSCs). Mesenchymal stem cells have many unique functions including the ability to inhibit inflammation following tissue damage, to secrete growth factors that aid in tissue repair, and to differentiate into many cell types including neural cells, bone cells, fat cells and cartilage

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JADICELL - Stem Cells: Regenerative Medicine For Longevity and Anti-age.

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Stem Cells: Regenerative Medicine For Longevity and Anti-age.

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Re: JADICELL -The Video Journal of Hematological Oncology (VJHemOnc).

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The Video Journal of Hematological Oncology (VJHemOnc).

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