Mesenchymal Stem Cell Therapy for Osteoarthritis: The Critical Role of the Cell Secretome

Mesenchymal Stem Cell Therapy for Osteoarthritis: The Critical Role of the Cell Secretome

Osteoarthritis (OA) is the most common form of arthritis, affecting over 525 million people around the world.  Characterized by pain, swelling, and stiffness resulting from the degradation of cartilage that provides cushion and protection between our bones, OA is an inflammatory condition without a clear and effective treatment.

OA most commonly affects the hands, knees, hips, and spine, but ultimately can cause damage to any joint in the body. Currently, most treatments for OA are designed to minimize the symptoms of the condition, not to treat or prevent the condition itself.

In recent years, pre-clinical studies of mesenchymal stem cells (MSCs) have demonstrated to be successful in resurfacing areas of degenerated cartilage and early-phase clinical trials found that intra-articular (IA) administration of MSCs leads to a reduction in pain and improved cartilage protection and healing.

In this review, Mancuso et al. provide an overview of the functions and mechanisms of MSC-secreted molecules found in in-vitro and in-vivo models of OA. Although MSCs disappear from the target area soon after administration, they have been found to demonstrate a rich secretory profile that is enhanced by exposure to inflammatory signals and is still able to deliver immunomodulatory effects.

Mancuso et al. highlight that, although chondrocyte apoptosis has long been associated with OA and despite the fact that there is no conclusive report identifying anti-apoptosis effects associated with MSCs, indirect evidence suggests that they have inhibited of ex-vitro cultured OA chondrocytes. Considering this, the authors recommend future studies of joint-associated MSC anti-apoptotic effects as a way to identify direct mediators of the process.

According to the authors of this review, the role of inflammation in the establishment and maintenance of OA is now widely accepted with synovial membrane inflammation a hallmark of OA pathology. Additionally, the biological markers of inflammation positively correlate with knee pain and clinical progression of OA. Studies have demonstrated that licensed MSCs secrete an array of anti-inflammatory cytokines which can help re-establish an equilibrium in the inflamed synovium and reduce inflammation in joints affected by OA.

After being administered, MSCs tend to undergo biological changes more radical than differentiation or licensing, with most completely disappearing 10 days post-injection. However, even after this occurs, there have been significant therapeutic effects observed.

Researchers have found that these apoptotic MSCs communicate with immune cells both directly and indirectly with patient responsiveness to MSCs correlating with their cytotoxic capacity.  Mancuso et al. conclude that these findings provide evidence that apoptosis is one of the driving mechanisms of MSC-mediated immunosuppression. 

Findings also suggest that the paracrine action of MSCs is not limited to soluble factors and has been shown to produce extracellular vesicles (ECVs). In pre-clinical models, ECVs have been observed to have anti-apoptotic, anti-fibrotic, pro-angiogenic, and anti-inflammatory effects. In addition, these ECVs – when derived from MSCs – inhibit the proliferation of lymphocytes, macrophages, and B cells.  

MSC-derived ECVs have shown to be promising in rat models of osteoporosis and have recently been tested in OA animal models with promising results. The authors point out that while further study is required, the initial findings indicate that the use of MSC-ECVs in therapy designed for OA would bring many advantages when compared to cell-derived products. The authors also point out that several issues with ECVs still have to be considered, including the need for them to be specifically tailored for the specific indication being treated.

Mancuso et al. conclude that MSCS has already proved to be a valuable tool for many conditions and there is significant potential for their use in OA. Phase I clinical trials have established that the direct IA administration of MSCs in OA patients is safe and pain reduction and increased cartilage thickness have been observed after injection. However, they also call for additional studies to examine the role of cell death in mediating the therapeutic effects of MSCs.

Source: Mesenchymal Stem Cell Therapy for Osteoarthritis: The Critical Role ….” 11 Jan. 2019, https://www.frontiersin.org/articles/10.3389/fbioe.2019.00009/full.

Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials.

Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials.

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/.

Effects of Mesenchymal Stem Cell-Derived Paracrine Signals and Their Delivery Strategies

Effects of Mesenchymal Stem Cell-Derived Paracrine Signals and Their Delivery Strategies

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.

Stem Cell Therapy for Multiple Sclerosis

Stem Cell Therapy for Multiple Sclerosis

Every year, stem cell therapy gains massive traction due to its incredible regenerative and auto-repair properties. More specifically, patients who deal with chronic, incurable conditions such as multiple sclerosis (MS) are closely following any news about this cutting-edge technology.

What is a stem cell?

A stem cell is a special biological entity that has unlimited differentiation potentials and can become any type of cell, hence is also called an undifferentiated cell. The body keeps a large number of these cells in different sites (e.g. bone marrow, umbilical cord, adipose tissue) in case it endures lesions that need regenerative capacities.

The fascinating feature of stem cells is their ability to differentiate into different cell types, including hepatocytes, nerve fibers, osteocytes, chondrocytes, and keratinocytes.

Are stem cells extracted from fetuses?

Perhaps the unethical aspect of stem cell therapy is the most commonly believed misconception out there. This is because early research focused on extracting stem cells from fetuses and embryos, which is what stuck with media outlets and the general population.

However, as mentioned earlier, stem cells are kept in the body to repair inflicted damage, allowing medical professionals to extract these cells and use them to manage a variety of conditions and their symptoms.

How do stem cells help with MS?

Multiple sclerosis is a chronic condition that’s caused by a type IV hypersensitivity reaction, which occurs when the immune system releases antibodies and specific cells to target a certain tissue. In the case of MS, the immune system attacks the myelin sheaths on nerve fibers that allow for fast bioelectrical transmissions of signals.

Stem cell therapy can potentially help MS progression and symptoms in two major ways:

Immunomodulating

By getting rid of the hyperactive immune cells and replacing them with new regulated ones, using stem cell therapy, the reaction against nerve fibers is potentially halted and symptoms may start to temper down.

Re-myelinization

Instead of targeting the immune system, stem cell therapy also helps by having the ability to regenerate myelin sheath. Note that the process of re-myelinization does not occur spontaneously without having progenitor cells to rely on.

In other words, if the patient does not receive stem cell therapy, the myelin sheaths that were destroyed in the relapse phase are irreversibly lost.

How long does it take for possible symptom improvement?

Typically, patients experience symptom improvement after several months of receiving therapy, with peaking results between the 3rd and 6th-month post-procedure. Some may experience feeling improvements earlier. The types of symptoms expected to improve include all signs that were triggered by multiple sclerosis-related inflammatory and immune reactions.

Is stem cell therapy superior to conventional treatment?

The answer to this question is not straightforward, as many factors fall into play. To keep it short, conventional therapy focuses on suppressing your immune system, which predisposes you to several infectious pathogens. Moreover, it cannot modulate the immune system nor regenerate the damage inflicted on the nerve fibers.

Incorporating stem cell therapy in the treatment of MS has opened a door to new opportunities to manage a condition that was initially thought incurable. It is important to remember that this is a management tool that can be done in conjunction with traditional medicine as well as healthy lifestyle choices.

Bone Marrow-Derived MSCs to Reduce Neural Damage and Prevent Multiple System Atrophy

Bone Marrow-Derived MSCs to Reduce Neural Damage and Prevent Multiple System Atrophy

Multiple system atrophy (MSA) is a rare, degenerative adult-onset neurological disorder that affects your body’s involuntary functions, including blood pressure, breathing, bladder function, and motor control. MSA also demonstrates several symptoms similar to those accompanying Parkinson’s disease, including slow movement, stiff muscles, and loss of balance[1].

Considering the rapid and fatal progression of MSA, there are not currently any long-term drug treatments known to produce therapeutic benefits against the condition. The typical neuropathological hallmarks of MSA are bone marrow destruction and cell loss in the striatonigral region of the brain that results in dopamine deficiency significant enough to result in behavioral abnormalities. 

Since mesenchymal stem cells (MSCs) have demonstrated the ability to self-renew and differentiate within a wide variety of tissues, Park et al., in this study, aimed to assess whether the transplantation of human-derived MSCs could have beneficial effects in a double-toxin-induced MSA rat model. Additionally, the authors assessed the signaling-based mechanisms underlying the neuroprotective effects of MSCs.

Specifically, as part of this study, Park et al. studied the effects of MSCs in 60 rats randomly allocated to one of six groups – a control group, a double-toxin group, two groups receiving MSC intra-arterial (IA) injections, and two groups receiving MSC transplantation via intrathecal (IT) injection after double-toxin induction.

After receiving treatment each group of rats underwent a variety of tests, including the Rotarod test, gait test, and grip strength test. Additionally, the brain tissue of the rats was collected, preserved, and evaluated to assess notable differences.

At the conclusion of this study, the authors found clear evidence of the protective effects of MSCs on double-toxin-induced MSA. The study also demonstrated that transplantation of MSCs prevented neuronal cell death and improved behavioral disorders caused by double-toxin-induced MSA, specifically by reducing dopaminergic neurodegeneration and neuroinflammation.

Additionally, Park et al.’s study demonstrated a higher expression of polyamine modulating factor-binding protein 1 and a lower expression of 3-hydroxymethyl-3-methylglutaryl-COA lyase (HMGCL) after MSC transplantation. 

Park et al. also point out that further investigation is required to better understand the exact mechanism of neuron-specific knockdown in vivo animal and clinical trials.

The authors of this study conclude that treating MSA with bone-marrow-derived MSCs protects against neuronal loss by reducing polyamine- and cholesterol-induced neural damage and may represent a promising new therapeutic treatment option for MSA.

Source: “Prevention of multiple system atrophy using human bone marrow ….” 11 Jan. 2020, https://stemcellres.biomedcentral.com/track/pdf/10.1186/s13287-020-01590-1.pdf.


[1] “Multiple system atrophy (MSA) – Symptoms and causes – Mayo Clinic.” 21 May. 2020, https://www.mayoclinic.org/diseases-conditions/multiple-system-atrophy/symptoms-causes/syc-20356153. Accessed 4 Apr. 2022.

Mesenchymal Stem Cells in Multiple Sclerosis: Recent Evidence from Preclinical to Clinical Studies

Mesenchymal Stem Cells in Multiple Sclerosis: Recent Evidence from Preclinical to Clinical Studies

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.

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