by admin | Jul 8, 2022 | Mesenchymal Stem Cells, Stem Cell Research
Human Mesenchymal Stem Cells (hMSCs) are the non-hematopoietic, multipotent stem cells with the capacity to differentiate into mesodermal lineages such as osteocytes, adipocytes, and chondrocytes as well ectodermal (neurocytes) and endodermal lineages (hepatocytes).
Until recently, when the immunomodulation properties of MSCs were proven to be clinically relevant, the use of these stem cells was met with skepticism and doubt by a large portion of the scientific community.
However, since that time, MSCs have demonstrated tremendous potential for allogeneic use in a number of applications, including cell replacement, and tissue regeneration, and for use in the therapeutic treatment of immune- and inflammation-mediated diseases. In fact, in many cases, the use of MSCs has been so successful that they appear to demonstrate more efficacy than what has been observed previously in traditional regenerative medicine.
Among the many benefits making MSCs so interesting for this application is their capacity for both multilineage differentiation and immunomodulation. Obtaining a better understanding of these capacities has opened new doors in regenerative medicine and demonstrated that these somatic progenitor cells are highly versatile for a wide range of therapeutic applications.
Additionally, the authors of this review point to research indicating the capacity of MSCs to home to the site of injury and/or inflammation, making them more attractive for use in clinical application. In this review, Wang et al. focus on this non-traditional clinical use of tissue-specific stem cells and highlight important findings and trends in this exciting area of stem cell therapy.
At the time this review was published, there were over 500 MSCs-related studies registered with the NIH Clinical Trial Database. Interestingly, nearly half of these trials involve attempts to better understand the use of MSCs in treating immune- and inflammation-mediated diseases – an indication of the recent shift in focus when determining effective therapeutic applications of MSCs.
In reviewing these clinical trials, Wang et al. found that the most common immune-/inflammation-mediated indications in MSC clinical trials were for graft-versus-host disease (GVHD), osteoarthritis (OA), obstructive airway disease, multiple sclerosis (MS), and solid organ transplant rejection.
Clinical trials involving MSCs, and specifically HSCs, in GVHD have indicated that while there may be indications of immunosuppressant therapy, immune rejection in the form of GVHD is still a major cause of morbidity and mortality, occurring in 30 ~ 40 % of allogeneic HSC transplantations.
Despite a number of clinical trials indicating significant efficacy in the use of MSCs for GVHD treatment, the authors point out that these findings were not observed consistently throughout all trials. Significant differences in these studies appeared to be related to differences in adult and pediatric applications, a specific type of HSC that was transplanted, and the type of MSCs that were utilized. There also appears to be a disparity in the results obtained from similar studies conducted in Europe and North America. Considering this, there are a number of studies involving MSCs and GVHD still ongoing.
These findings led the authors to conclude that despite the strong potential of MSCs as therapeutic agents for GVHD, detailed tailoring of the patient population and stringent MSC processing criteria are necessary to deliver consistent and reproducible results.
Despite the mixed findings for use of MSCs in the treatment of GVHD, trials reviewed for other immune/inflammation-mediated diseases, including MS, inflammatory bowel disease, OA, RA, and inflammatory airway and pulmonary diseases demonstrated positive results pertaining to the safety of MSC therapy when used in this application.
Specifically, Wang et al. point out that although there have been positive results observed in preclinical animal studies, these results have not translated to clinical efficacy. In considering this, the authors suggest a focus on better clarifying pathophysiological details and subsets within disease entities to better tailor MSC therapy and standardization of in vitro culture protocols with stringent criteria for testing of functional parameters as two important steps to improve our understanding on the mechanistic properties of MSC immunomodulation.
Despite these recommendations, the authors conclude that the current results and developments of these clinical trials demonstrate that the tremendous potential of MSC therapy in a wide range of areas, including the treatment of immune/inflammation-mediated diseases, can be expected in the near future to achieve clinical relevance.
Source: “Human mesenchymal stem cells (MSCs) for treatment towards ….” 4 Nov. 2016, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095977/.
by admin | Jun 24, 2022 | Mesenchymal Stem Cells, Exosomes, Stem Cell Research, Stem Cell Therapy
Mesenchymal stem cells (MSCs) have been widely studied and increasingly recognized as a potential therapeutic with the ability to initiate and support tissue regeneration and remodeling. While over 1100 clinical trials have been conducted to assess the therapeutic benefits of MSCs, there continues to be widespread variation surrounding the potential treatment outcomes associated with these cells.
This review, authored by Chang, Yan, Yao, Zhang, Li, and Mao, focuses primarily on profiling the effects of the secretome, or the effects of paracrine signals of MSC, as well as highlights the various engineering approaches used to improve these MSC secretomes. Chang et al. also review recent advances in biomaterials-based therapeutic strategies for the delivery of MSCs and MSC-derived secretomes.
Recent research has demonstrated paracrine signaling as the primary mechanism of MSC therapeutic efficacy. This shift towards the MSC secretome in applications ranging from cartilage regeneration to cardiovascular and other microenvironments has demonstrated its therapeutic potential in prevalent injury models. Additionally, the versatility of MSCs allows them to be specifically tailored using biomaterials toward specific therapeutic outcomes.
A specific example of MSC secretome’s therapeutic potential is their ability to support cardiovascular tissue repair through minimization of fibrotic scarring of cardiac tissue typically observed to occur during a myocardial infarction (MI). Additionally, research has demonstrated MSC secretomes facilitate the proliferative, angiogenic, and anti-inflammatory phases of the wound healing process.
Secretome transfer occurring between MSCs and other cells in the target area primarily occurs through the release of extracellular vesicles (EVs) and is considered a safer form of therapeutic application compared to MSC therapy. MSC secretomes can also be specifically engineered through hypoxia, treatment with bioactive agents, and modulating cell-cell and ECM interactions in the MSC culture.
One of the biggest challenges facing the therapeutic efficacy of MSC is their limited cell survival, retention, and engraftment following injection or transplantation (found to be as low as 1% surviving one day after implantation). Recent studies have demonstrated MSC secretome, and specifically, EVs, although they remain a significant obstacle, are a promising alternative and able to bypass a number of cellular challenges, including cell survival.
Further consideration and approaches to increasing survival rates of MSCs include experimenting with a wide variety of biomaterials as a way to promote adaptation in the target implantation area. This includes looking for biomaterials to regulate oxygen tension levels, glucose supply, mechanical stress, and pH levels, which collectively can be used to regulate metabolic pathways of the MSC, effectively influencing cell survival and their ability to be used as therapeutic treatment options.
Despite the recent advances in the use of MSC secretomes and their delivery strategies, Chang et al. call for continued study of the subject and specifically recommend developing a specific set of paracrine cues to be used as a well-defined formulation in future therapeutic applications.
The authors also point out that the use of EVs and other direct applications of the MSC secretome are thought to be promising for the treatment of osteoarthritis, ischemic stroke, and coronavirus-related diseases. Considering this, Chang et al. highlight the increasing need to fully understand the paracrine signaling effects of MSC therapies and the delivery strategies associated with this application.
Source: “Effects of Mesenchymal Stem Cell‐Derived Paracrine Signals and ….” 12 Jan. 2021, https://onlinelibrary.wiley.com/doi/full/10.1002/adhm.202001689.
by admin | Jun 3, 2022 | Parkinson's Disease, Stem Cell Research
Research has shown neuroinflammation to have a significant role in the pathogenesis of Parkinson’s disease (PD). Much of this same research has also demonstrated mesenchymal stem cells (MSCs), and specifically, allogeneic bone marrow-derived MSCs, can be effectively used as an immunomodulatory therapy for the potential treatment of PD.
The goal of Schiess et al.’s study was to evaluate the safety and tolerability of first-of-its-kind intravenous allogeneic bone marrow-derived MSCs (allo-hMSCs) in patients with PD.
Neurological disorders continue to be the leading cause of disability-adjusted life years lost worldwide (a statistical measure of years of healthy life lost as a result of death or disability relating to the constitution). While the numbers of those diagnosed with neurological disorders, including stroke, multiple sclerosis, motor neuron disease, and dementia continue to increase at a rapid rate, none are growing as fast as PD.
Considering the rapid progression of progressively intensifying symptoms associated with PD and the relatively poor progress in the discovery of therapies to prevent, or even slow, progression of PD, the authors identified the identification of effective and safe disease-modifying therapies for PD to be a priority.
As part of this study, Schiess et al. studied the peripheral immune system in PD neurodegeneration through the evaluation of LPS rat models, glial cells, and cerebrospinal fluid gathered from patients. As a result of these investigations, the authors determined that an adaptive immune response does contribute to progression supporting the rationale for using MSCs as a potential therapy for PD.
To evaluate the effectiveness of this therapy, Scheiss et al. developed and conducted a single-center, open-label, ascending-dose-escalation phase 1 clinical study involving 20 patients with mild to moderate PD. Participants were assigned to single intravenous doses of 1 of 4 doses and evaluated at weeks 3, 12, 24, and 52 post-infusion.
In addition to evaluating the safety and tolerability of an intravenous infusion of bone marrow-derived allow-hMSCs, the research team also evaluated participants for relevant biomarkers for the mechanism of action and clinical assessment of PD progression.
The authors point out that while there were no serious adverse reactions related to the infusion and no responses to donor-specific human leukocyte antigens, the most commonly reported side effect was dyskinesias and hypertension. Further studies will need to monitor the emergence or exacerbation of post-infusion dyskinesias and hypertension to better understand their occurrence as part of this study.
In conclusion, Sheiss et al. found that a single infusion of allogeneic MSCs ranging from 1 to 10×106 intravenous allo-hMSCs/kg was safe, well tolerated, and not immunogenic in patients with mild-to-moderate PD. The authors also found that peripheral inflammation markers appeared to be reduced at 52 weeks after receiving the highest dose, leading to the conclusion that the highest dose had the most significant effect at the 52-week interval.
Based on these findings, the authors recommend moving forward with a phase 2 randomized, placebo-controlled efficacy trial using allo-hMSCs in a larger population of well-defined Parkinson’s disease patients.
Source: “Allogeneic Bone Marrow-Derived Mesenchymal Stem Cell Safety in ….” 27 Mar. 2021, https://movementdisorders.onlinelibrary.wiley.com/doi/full/10.1002/mds.28582.
by admin | May 6, 2022 | Stem Cell Therapy, Mesenchymal Stem Cells, Multiple Sclerosis, Stem Cell Research
Multiple sclerosis (MS) is a chronic inflammatory disease that attacks myelin, the protective sheath that covers nerves and causes progressive and serious communication issues between the brain, central nervous system, and the rest of the body[1].
Currently, it’s estimated that over 2.3 million people worldwide, and over one million people in the US have a diagnosis of MS[2].
While there have been significant improvements in treatments designed to stabilize, delay, and even improve symptoms of MS, new and more effective treatments are needed to improve the long-term outcome associated with the condition.
One area currently being investigated as a potential therapeutic option for treating MS is the use of regenerative medicine, also known as stem cell therapy, and specifically treatment using mesenchymal stem cells (MSCs).
In this review of evidence from preclinical and clinical studies, Gugliandolo et al. examine studies involving the use of MSCs or their derivatives in vivo models of MS and patients affected by MS. The authors also examine and discuss the feasibility of autologous MSCs therapy for MS patients.
Specifically, and when assessed in terms of effectiveness when treating MS, the therapeutic potential of MSCs was associated with their differentiation capacity and paracrine effects, their ability to differentiate toward oligodendrocytes and express oligodendrocyte progenitor cell (OPC) markers, and their capacity for homing (moving towards the damaged area following chemical gradients).
As part of this review, the authors also examined the effectiveness of various sources of MSC in MS models, these sources included bone marrow MSCs (BM-MSCs), adipose tissue-derived MSCs (AD-MSCs), periodontal ligament stem cells (PDLSCs), skin-derived MSCs (S-MSCs), Wharton’s jelly-derived MSCs (WJ-MSCs), human umbilical cord MSCs (UCMSC), human amnion mesenchymal cells (AMCs), placental derived MSCs (PMSCs), and decidua derived MSCs (DMSCs). According to the research reviewed by Gugliandolo et al., all MSCs, regardless of where they were harvested from, demonstrated beneficial effects in the therapeutic treatment of MS.
Specifically, the results demonstrated that MSCs were able to produce some form of protective effects in reducing inflammatory cell infiltration, disease score, demyelination, and blood-brain barrier disruption.
A review of 29 phase 1 or 2 clinical trials registered on clinicaltrials.gov demonstrated that MSCs, regardless of the type and method of administration, demonstrated to be safe and absent of severe adverse effects with the majority demonstrating measurable improvements when used in MS patients.
While clinical trials demonstrated the safety of administration of MSC in MS patients, the authors were particularly interested in learning if autologous MSC transplantation presented some advantages over heterologous administration.
The authors of this review found that samples obtained from healthy controls and MS patients showed similar features, indicating the possibility of autologous stem cell therapy in MS patients. However, other studies found that MSCs obtained from MS patients exhibited a different transcriptional pattern and fewer immunosuppressive functions compared to healthy donor MSCs.
Gugliandolo et al. point out that limits to these experimental studies include the use of animals of a single gender, given that sex-dependent differences exist and the use of different MS models, different number of transplanted cells, different MSCs sources, and routes of administration. These limitations make it difficult to define the optimal treatment in terms of cell type, dose, and administration conditions.
The authors conclude that clinical trials demonstrate the safety and feasibility of MSCs treatment, and also some improvements, but more data on larger cohorts are required to establish their efficacy. Considering the controversial results pertaining to the features of MSCs derived from MS patients, the authors also call for additional research in order to conclusively determine the safety and efficacy of autologous MSCs therapy in MS patients.
Source: “Mesenchymal Stem Cells in Multiple Sclerosis – NCBI.” 17 Nov. 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698327/.
[1] “Multiple sclerosis – Symptoms and causes – Mayo Clinic.” 7 Jan. 2022, https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269.
[2] “Understanding MS | National Multiple Sclerosis Society.” https://www.nationalmssociety.org/What-is-MS/MS-FAQ-s.
by Stemedix | Apr 11, 2022 | Parkinson's Disease, Mesenchymal Stem Cells, Stem Cell Therapy
Regenerative medicine, also known as stem cell therapy, is emerging as a viable treatment for Parkinson’s disease as clinical trials move through the FDA approval process. Patients in clinical trials see positive results from mesenchymal stem cell therapy for Parkinson’s Disease.
What Is Parkinson’s Disease?
Parkinson’s disease is a progressive, neurodegenerative condition. It occurs when dopamine-producing brain cells stop working or die. Dopamine’s role in the body is to send messages between nerve cells or from nerve cells to muscle cells, affecting the body’s physical and mental functions.
Symptoms of Parkinson’s start gradually, and the disease worsens over time. Early symptoms include tremors in the hands, rigidity, and slowness of movement. Patients with Parkinson’s also experience difficulty with balance, and eventually, with speech, writing, and automatic muscle movement such as blinking.
While there’s currently no cure for Parkinson’s, there are medications that patients can take to manage symptoms. Some symptoms are also relieved from surgery to regulate specific brain areas.
Patients with Parkinson’s disease experience a progressive decline in their ability to function, with treatments only offering some relief. The emergence of mesenchymal stem cell therapy as an option to reverse the damage and halt the progression of Parkinson’s disease is an exciting development.
What Are Mesenchymal Stem Cells?
Stem cells are considered to be the building blocks of cells. All specialized cells in the body come from stem cells. When stem cells divide, they either produce more stem cells, called daughter cells, or differentiate into specialized cells, such as bone, blood, or brain cells.
Mesenchymal stem cells (MSCs) are adult stem cells commonly found in bone marrow. They also exist in adipose (fat), umbilical cord tissue, amniotic fluid, and other locations. MSCs remain dormant in the bone marrow until they’re needed to facilitate healing in the body.
MSCs differentiate into:
- Bone cells
- Muscle cells
- Skin cells
- Cartilage
- Neural cells
- Corneal cells
MSCs are present throughout your life, but they age as the body ages, making them less effective and concentrated over time.
How Can Mesenchymal Stem Cells Benefit Those with Parkinson’s Disease?
In recent clinical trials using mesenchymal stem cells on Parkinson’s patients, the cells significantly improved patients’ symptoms, including facial expressions, gait, and rigidity or “freezing” episodes. Some of the patients in this study substantially reduced their dosages of medicines used to control Parkinson’s symptoms.
In a 2005 study, researchers determined that stem cells may be capable of differentiating into dopamine neurons, which are damaged or destroyed with Parkinson’s.
While the true potential of mesenchymal stem cell benefits in Parkinson’s patients is still being investigated, there is reason to believe that patients with the neurodegenerative condition could experience a significant improvement in their quality of life with stem cell therapy. If you are interested in learning more about Mesenchymal Stem Cell Therapy for Parkinson’s Disease, contact us today at Stemedix!
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