Mesenchymal stem cells (MSCs) are multipotent fibroblast-like cells found throughout the body and have been found to have self-renewing and multilinear therapeutic potential by providing new cells for tissue repair by replacing damaged cells.
Thought to stimulate repair and control the immune response through an expression of growth factors and other cytokines, MSCs are at low risk of rejection and repair tissue damage through immunomodulation, not by their ability to differentiate.
While MSCs can be isolated from a number of tissue sources, including bone marrow, peripheral blood, adipose (fat) tissue, umbilical cord blood, and umbilical cord tissue (Wharton’s jelly). MSCs derived from the human umbilical cords (UCMSCs) have been found to have significant advantages over MSCs isolated from other sources. These advantages include higher proliferation and self-renewal capacity and multilineage differentiation capability.
Unlike many sources of MSCs, the umbilical cord is considered medical waste, making the collection of UCMSCs noninvasive and eliminating ethical concerns associated with the collection of MSCs from other sources. These UCMSCs have been developed as effective “off-the-shelf” cell therapy for a number of conditions, including autoimmune diseases, and as a treatment for a number of emergency medical conditions.
This Phase 1 clinical study, designed and conducted by Chin et al., intended to determine the safety and efficacy of intravenous allogeneic infusion of UCMSCs in healthy volunteers and to determine the effective dose at which an immunomodulatory effect is observed. The findings of this study are intended to serve as a guideline and benchmark for future CVL-100 clinical research.
Analyzing the results of this clinical study, the authors report that there was no observed complication resulting from the infusion and no significant adverse event in either dosage group in the 6 months of follow-up. These findings led Chin et al. to conclude that UCMSCs infusion was safe among healthy subjects, results that were consistent with other UCMSC treatment-based studies.
The authors also reported that UCMSCs infusion posed no significant adverse effects in patients with type 2 diabetes. Despite the relatively small sample group of this study (11 subjects), the authors reported demonstrating an initial transient proinflammatory effect followed by a significant and prolonged anti-inflammatory effect.
In addition, Chin et al. report found that high-dose (HD) CLV-1000 infusion provided a significant increase in both hemoglobin level and MCV level that falls within the normal range. Biomarker assessment results also indicated that the HD group demonstrated a significant steady increase of cytokine IL-1RA from baseline up until 6 months of posttreatment. This finding is especially important as IL-1RA is a naturally occurring antagonist to the proinflammatory cytokine 1L-1.
The authors conclude that this study clearly demonstrates a difference in immunomodulatory effect between the high-dose and low-dose treatment groups, with the HD group demonstrating a significantly greater reduction of proinflammatory cytokine TNF-α and an increased level of specific anti-inflammatory cytokines within 6 months and in relation to those in the low dose group. Considering this, Chin et al. conclude that a CLV-100 dosage of two million MSCs per kilogram of body weight represents the optimal dose level for overcoming inflammatory conditions by displaying the best improvement in all parameters tested, absence of side effects, and SAEs.
The data collected in this study also suggests that this is the first study to report a significant reduction of globulin observed over the course of the study. This is important because globulin serves an important role in immunity. Additionally, increases in serum globulins are associated with several immune-mediated diseases, including rheumatoid arthritis, chronic liver disease, diabetes mellitus, and cancer.
Considering these findings, the authors of this study conclude that high doses of allogeneic MSCs could help exert beneficial effects of repair and healing.
Articular cartilage, found on the surface of most musculoskeletal joints, distributes and transfers forces between bones and joints, provides a smooth surface for joint mobility, and plays an important role in human mobility.
However, articular cartilage is also easily susceptible to damage, but difficult to repair itself on its own (primarily due to the fact it is mostly avascular). Over time, the inability of articular cartilage to repair itself leads to progressive joint pain, disfigurement, movement disorders, and ultimately osteoarthritis.
The CDC estimates that nearly 33 million Americans are currently affected by osteoarthritis, most often in the form of pain, stiffness, decreased mobility and range of motion, and swelling in the joints[1].
Current treatment methods, including microfracture technology, autologous or allogeneic cartilage transplantation, and autologous chondrocyte implantation (ACI) have demonstrated the ability to repair and regenerate fibrous cartilage, but not articular cartilage required for smooth, fluid, natural mobility.
To address this issue, recent research has focused on the efficacy of stem cells, and specifically mesenchymal stem cells (MSCs) found in bone marrow, adipose tissue, synovial membrane, and umbilical cord Wharton’s jelly, as potential therapeutic treatments for regeneration of articular cartilage. MSCs are particularly of interest due to their demonstrated abilities of self-renewal, multi-differentiation, and immunoregulation.
While the use of MSCs has demonstrated tremendous potential in the field of regenerative therapy, one notable drawback continues to be unstable or suboptimal results resulting from the heterogeneity of various mesenchymal stem cells.
Specifically, the stability and efficacy of MSCs appear to differ based on a number of factors, including the donor, the tissue source, and their ability for proliferation, differentiation, and immunoregulation.
For example, some of the key heterological differences highlighted in this review include the efficacy of MSCs based on donor’s age (with younger donors providing higher quality MSCs), Wharton’s Jelly MSCs showing greater prospects for application in cartilage regeneration than other MSCs, and differences within specific MSC subpopulations.
The authors of this review acknowledge the potential of MSCs in repairing arterial cartilage, but also point out that there needs to be a deeper understanding of the heterogeneity of various MSCs in order to improve the efficiency of MSC-based therapies designed to repair arterial cartilage. In addition, the authors also call for greater standardization in MSC isolation and harvesting methods among laboratories in order to provide better consistency with respect to results obtained from studies using MSCs.
Perinatal stem cells have been attracting attention globally in recent years due to their potential in regenerative medicine. These stem cells come in many forms, due to the wide variety of potential sources for these cells. Perinatal stem cells, for instance, may be umbilical cord-derived hematopoietic stem cells, amniotic epithelial cells, amniotic fluid stem cells, or chorionic mesenchymal stem cells. All sources, nonetheless are considered biological waste and are therefore usually discarded after delivery of babies.
Importantly, perinatal stem cells, despite their origin, tend to share a number of characteristics that make them beneficial in treating conditions. Additionally, unlike other sources of stem cells, retrieval of perinatal stem cells is noninvasive and does not require the ethical considerations that retrieval from other sources may involve. A recent review in Regenerative Medicine has highlighted the potential benefits of perinatal stem cells in therapeutic interventions.
In addition to the relatively easy collection and preparation of perinatal stem cells, these cells tend to be easily harvested and manipulated without harming either the mother or the baby. Upon collection, these stem cells exist in high volume and have greater ability to proliferate than other stem cell types such as bone marrow stem cells. Research has also shown that these cells tend not to lead to adverse immune reactions, though the mechanisms involved in their relationship to the immune system are not well understood.
Given their relative advantages over other stem cell types, perinatal stem cells are well poised to be used in cell-based therapies targeting a wide variety of conditions. Future research will help to define the precise role these cells can play in regenerative medicine and which conditions they may be most useful for.
Wharton’s jelly is a rather unique body fluid. It is the connective tissue found within the umbilical cord. While Wharton’s jelly is connective tissue, it more closely resembles gelatin. Historically this material was discarded as medical waste; however, Wharton’s jelly has been shown to contain a number of therapeutic substances. Among these healing substances found within Wharton’s jelly is an abundant supply of mesenchymal stem cells.
One of the most intriguing features of Wharton’s jelly is that it contains a virtually limitless supply of mesenchymal stem cells. There are about 4 million new births in the United States each year, 5 million in the European Union, and over 100 million worldwide. The potential pool of cells is staggering when you consider only a small amount of Wharton’s jelly can contain millions of stem cells. Notably, Wharton’s jelly is usually discarded after the delivery of a healthy baby. If this material could be donated instead of discarded, researchers believe they have found an abundant, renewable resource from which to draw mesenchymal stem cells.
However, the abundance of Wharton’s jelly is not the most impressive feature of the substance. The stem cells found in Wharton’s jelly are rather unique. Perhaps most importantly, the cells are immuno-privileged. This means they are not readily recognized by the immune system. Consequently, the stem cells can be taken from the umbilical cord, purified, and then injected into a patient with little risk of the patient having an immune reaction to the cells. These particular mesenchymal stem cells are also interesting because they are relatively “primitive,” which means they have some of the same properties of embryonic stem cells. However, Wharton’s jelly can be obtained without controversy, while harvesting embryonic stem cells from aborted tissue remain highly controversial.
Stem cells taken from Wharton’s jelly are already being used in some clinical studies. For example, researchers in one clinical study injected type 2 diabetes patients with Wharton’s jelly-derived mesenchymal stem cells. Within six months of treatment, 7 of 22 patients became insulin-free and 5 were able to reduce the amount of insulin they needed by more than 50%. Only one patient out of the 22 did not respond to the stem cells at all. The cells have also been tested in systemic lupus erythematosus, better known as simply lupus. Forty patients received Wharton’s jelly mesenchymal stem cells intravenously. Thirteen patients enjoyed a major clinical response while 11 enjoyed a partial clinical response of their lupus symptoms.
As more clinical studies are done on Wharton’s jelly-derived mesenchymal stem cells, we will learn what other diseases can be treated with this once-discarded substance. Early indications show a very promising future.
Mesenchymal stem cells have been showing promise in the treatment of a variety of diseases and injuries. These cells are derived from different tissue types, and it appears that where the stem cells come from is indicative of how they function and how appropriate they are for use in different applications. Bone marrow-derived mesenchymal stem cells have been deeply studied and are often considered a go-to for stem cell research and clinical use.
However, there are several limitations that bone marrow-derived mesenchymal stem cells pose, particularly from a practicality standpoint, and thus, researchers have begun to try to understand how other types of stem cells may achieve similar or better results than those from the bone marrow. A recent review, published in Act Histochemical, compiled comprehensive data on the biological properties associated with a specific type of mesenchymal stem cell called Wharton’s Jelly-derived mesenchymal stem cells.
These stem cells, which come from the umbilical cord, are able to differentiate into mature cells that make up several different types of tissues and can even turn into non-mesenchymal cells, such as neurons, or brain cells. They are useful in that they spontaneously move to sites of injury or inflammation and may, therefore, be able to help restore tissue and normal functioning. They are also unlikely to instigate adverse immune system reactions.
While it is advantageous that bone marrow-derived mesenchymal stem cells have been studied extensively and therefore are associated with broad knowledge of therapeutic applicability, the cells are difficult to isolate and use. In contract, cells from the umbilical cord matrix, or Wharton’s jelly, are easy to isolate and also appear to be good candidates for therapeutic intervention. Future research should therefore look more closely at how Wharton’s jelly-derived mesenchymal stem cells can be used to treat disease and injury. As noted by the authors of this review, there are specifically dysfunctions of the central and peripheral nervous system that these stem cells may be able to address.
Mesenchymal stem cells that come from different cell sources can look similar but behave differently. Bone marrow-derived mesenchymal stem cells tend to be the gold standard for isolating and using mesenchymal stem cells, it is not particularly easy to access these cells from the bone marrow. Because there are other, much more easily accessible mesenchymal stem cells, such as those from the umbilical cord, it is important to establish the differences between the different types of stem cells so that each can be used when most appropriate and when most advantageous.
One important difference is how to isolate the cells and how easy it is to do so. Recent work published this year in Stem Cells and Development helped to define the best way to isolate mesenchymal stem cells from the Wharton’s jelly of umbilical cords. The researchers also looked at the gene expression profile and the immune system characteristics of both bone marrow-derived mesenchymal stem cells and Wharton’s jelly-derived mesenchymal stem cells.
The researchers found that mesenchymal stem cells that came from the Wharton’s jelly of the umbilical cord had a better capacity to expand into more tissue than those taken from the bone marrow. Further, their gene expression was different. In the stem cells from the Wharton’s jelly, there was greater gene enrichment for genes related to cell adhesion, proliferation, and immune system functioning than in the cells from the bone marrow. These cells also induced the maturation of brain cells more so than did the mesenchymal stem cell derived from bone marrow.
These results show that Wharton’s jelly-derived mesenchymal stem cells have distinct properties from bone marrow-derived mesenchymal stem cells and likely have specific advantages as well to help treat those battling osteoarthritis, multiple sclerosis, Parkinson’s disease, and other degenerative conditions. Further research will help bear out more of the differences between these types of stem cells and how each type can best be used to help patients.
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