Important new mesenchymal stem cell therapies

While embryonic stem cell therapies are still barely getting off the ground (see the post It’s a long  way to stem cell treatment), several important therapeutic applications of Mesenchymal stem cells (MSCs) are now getting to be well along in the development pipeline and could soon become part of mainline medicine.  

In this post I first enumerate some recently-discovered and exciting properties of MSCs that make these applications possible.  Then, to illustrate that mesenchymal stem cell therapies are going prime-time, I provide a current listing of clinical trials involving MSCs with hyperlinks to further information about each trial.     

Mesenchymal stem cells are multipotent cells that can differentiate into a variety of cell types including chondrocytes, osteoblasts,  myocytes, adipocytes and beta-pancreatic islets cells.  “Mesenchymal stem cells (MSC) represent a population of the bone marrow microenvironment, which participates in the regulation of haematopoietic stem cells (HSC) self-renewal and differentiation. MSC are multipotent non-haematopoietic progenitors, which have been explored as a promising treatment in tissue regeneration(ref).” Some of the properties of these cells are amazing, making them a good platform for a variety of new emerging disease therapies. 

Properties of Mesenchymal stem cells 

·        “MSCs are rare in bone marrow, representing approximately 1 in 10,000 nucleated cells. Although not immortal, they have the ability to expand manyfold in culture while retaining their growth and multilineage potential(ref).”

·        MSCs inhibit immune response.  “Both in vitro and in vivo, the MSC inhibit the T, B, NK and dendritic cell functions(ref).” MSCs suppress lymphocyte proliferation(ref).   Implications are that MSCs might be useful in treating autoimmune diseases,  and that MSCs could work in treating Graft vs Host Disease (GvHD), a major problem encountered in organ transplantation.

·        Because of their freedom from immune responses, MSCs work fine no matter where you get them.  “ Most interestingly, there was no difference in the response rates or side effects between patients receiving mesenchymal stem cells from third-party mismatched donors compared with those patients receiving cells from HLA-identical siblings or from haploidentical family members(ref).

·        MSCs tend to inhibit the inflammatory response. “Based on the observations that mesenchymal stem cells (a) develop into joint tissues and (b) in vitro and in vivo show immunosuppressive and anti-inflammatory qualities indicating a transplant-protecting activity, these cells are prominent candidates for future tissue engineering approaches for the treatment of rheumatic diseases(ref).”

·        MSCs prolong the survival of haemopoietic stem cells(ref).

·        MSCs automatically home in on diseased or damaged tissues requiring regeneration.  “It has been shown that MSCs, when transplanted systemically, are able to migrate to sites of injury in animals, suggesting that MSCs possess migratory capacity. However, the mechanisms underlying the migration of these cells remain unclear(ref).”

·        Arriving at a site having tissue damage and requiring regeneration, MSCs can and “know how to” differentiate into a variety of different types of cell tissues as needed, ranging from heart muscle cells to cartilage osteoclasts, and integrate themselves into a functioning organ so as to renew it.  

·        A 2010 study suggests that one of the communications strategies utilized by MSCs is that they they secrete therapeutic paracrine factors (signaling molecules that affect nearby cells) and also secrete RNA-containing microparticles(ref).

·        There is strong evidence that a number of known medical conditions can be treated with MSCs, and new ones are still being discovered.  “Experimental and clinical data gave encouraging results, showing that MSC injection allowed controlling refractory GVHD, restoring bone development in children with osteogenesis imperfecta or improving heart function after myocardial infarction(ref).”

·        Amazingly, Chondrogenic potential of human adult mesenchymal stem cells is independent of age or osteoarthritis etiology.  This means that the MSCs from an old person with osteoarthritis whose knee or hip cartilage is severely eroded by that osteoarthritis can be used to regenerate new cartilage.  “We conclude that, irrespective of age and OA etiology, sufficient numbers of MSCs can be isolated and that these cells possess an adequate chondrogenic differentiation potential. Therefore, a therapeutic application of MSCs for cartilage regeneration of OA lesions seems feasible.”  This will be the subject of another blog post to follow within a few days.

·        Several non-surgical ways are being experimented with for working with MSCs including site injection, topical application possibly with a structure matrix, and injection with substances that accelerate the natural migration of MSCs to a site requiring restoration. “Harnessing the migratory potential of MSCs by modulating their chemokine-chemokine receptor interactions may be a powerful way to increase their ability to correct inherited disorders of mesenchymal tissues or facilitate tissue repair in vivo(ref).” 

·        I even speculate that one of the main ways acupuncture could work is by creating minor damage that generates chemical messages that attract MSCs to an injury site requiring attention.

Previous blog posts have highlighted various aspects and other potential applications of MSCs.  See the blog posts Terminator stem cells in the early pipeline, Stem cell differentiation and nanotubes, Trojan-horse stem cells might offer an important new cancer therapy.  The blog post State of autologous stem cell therapies is relevant.  However it is already partially obsolete though only 8 months old.  Also, MSCs can be found in other body locations besides bone marrow, like in teeth.  See the post Dental Pulp Stem Cells – the big needle vs the tooth fairy.

Clinical trials involving Mesenchymal stem cells 

A good sign that  a drug or technology is probably headed for big-time medical use is when it is in several clinical trials.  The following  listing is mostly based in information from www.clinicaltrials.gov, “a registry of federally and privately supported clinical trials conducted in the United States and around the world.”  Clicking on any trial heading will lead you to further information about the objectives, methodology and status of the trial involved.   

1.     Safety Study of Adult Mesenchymal Stem Cells (MSC) to Treat Acute Myocardial Infarction  Also see ref.

2.     A Phase I Clinical Trial of the Treatment of Crohn’s Fistula by Adipose Mesenchymal Stem Cell Transplantation

3.     Mesenchymal Stem Cell Transplantation in Decompensated Cirrhosis

4.     Allogeneic Mesenchymal Stem Cell for Graft-Versus-Host Disease Treatment (MSCGVHD

5.     Mesenchymal Stem Cell Infusion as Treatment for Steroid-Resistant Acute GVHD or Poor Graft Function

6.       Prochymal™ Adult Human Mesenchymal Stem Cells for Treatment of Moderate-to-Severe Crohn’s Disease

7.     Safety and Efficacy Study of Umbilical Cord Blood-Drived Mesenchymal Stem Cells to Promote Engraftment of Unrelated Hematopoietic Stem Cell Transplantation (for treating acute leukemia).     

8.  Mesenchymal Stem Cell Infusion as Prevention for Graft Rejection and Graft-Versus-Host Disease (for treating Hematological Malignancies)

9.     Mesenchymal Stem Cells and Subclinical Rejection (related to Organ Transplantation)

10.            Autologous Transplantation of Bone Marrow Mesenchymal Stem Cells on Diabetic Foot

11.   Allogeneic Mesenchymal Stem Cells Transplantation for Primary Sjögren’s Syndrome (pSS)

12.            Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS)

13.            Mesenchymal Stem Cells in Critical Limb Ischemia

14.            The Use of Autologous Bone Marrow Mesenchymal Stem Cells in the Treatment of Articular Cartilage Defects (for treating Degenerative Arthritis; Chondral Defects;  Osteochondral Defects)

15.  Safety and Efficacy Study of Allogenic Mesenchymal Stem Cells to Treat Extensive Chronic Graft Versus Host Disease ((for combined treatment with prednisone and cyclosporine as primary treatment) 

16.            Mesenchymal Stem Cell Transplantation in the Treatment of Chronic Allograft Nephropathy  (for Kidney Transplant; prevention of Chronic Allograft Nephropathy)

17.            Extended Evaluation of PROCHYMAL[tm] Adult Human Stem Cells for Treatment-Resistant Moderate-to-Severe Crohn’s Disease

18.  Autologous Transplantation of Mesenchymal Stem Cells (MSCs) and Scaffold in Full-Thickness Articular Cartilage (for treating Knee Cartilage Defects;   Osteoarthritis)

19.            Evaluation of the Role of Mesenchymal Stem Cells in the Treatment of Graft Versus Host Disease

20.            Mesenchymal Stem Cell for Osteonecrosis of the Femoral Head

21.            Mesenchymal Stem Cells Under Basiliximab/Low Dose RATG to Induce Renal Transplant Tolerance

22.            Intravenous Stem Cells After Ischemic Stroke

23.            Effect of Mesenchymal Stem Cell Transplantation for Lupus Nephritis

24.            Safety and Efficacy Study of Adult Human Mesenchymal Stem Cells to Treat Acute GHVD

This listing may not be complete but should make the point that MSC therapies are probably heading for big-time.  Yet, I need point out that most of these trials are either just getting off the ground or are Phase I studies focused on safety and dosage rather than on efficacy.  And some of the trials could produce negative results and be aborted.  So it may be a while before most of these therapeutic applications are actually integrated in as part of mainline medicine. 

A few of the studies are in or already beyond Phase II, however, and moving along nicely through the pipeline.  The following is from a report in Medical News Today on a Phase II study:  “A phase II multicenter study performed within the European Group for Blood and Marrow Transplantation (EBMT) Mesenchymal Stem Cell Expansion Consortium, shows that mesenchymal stem cells provide a therapeutic potential for the treatment of acute steroid-refractory GvHD (graft-versus-host disease). — Allogeneic stem-cell transplantation is the treatment of choice for many malignant and non-malignant disorders. Severe graft-versus-host disease (GvHD) is a life-threatening complication which could arise following this treatment. Especially if patients with GvHD do not respond to steroids, therapeutic options are limited and the success uncertain. This publication in one of the leading scientific journals opens new exciting possibilities for patients with GvHD. — The study was launched to assess whether mesenchymal stem cells could reduce the risk of GvHD after stem cell transplantation. Between October 2001 and January 2007, 55 patients were treated. From this, 30 patients had a complete response and nine showed improvement. No patients had side effects during or immediately after infusions of mesenchymal stem cells. This response was not related to donor HLA-match. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. — This phase II study shows that the infusion of mesenchymal stem cells expanded in vitro, irrespective of donor, might be an effective therapy for patients with steroid-resistant, acute GvHD. Most interestingly, there was no difference in the response rates or side effects between patients receiving mesenchymal stem cells from third-party mismatched donors compared with those patients receiving cells from HLA-identical siblings or from haploidentical family members. This finding makes the logistical requirements for this approach more convenient, because the establishment of local banks of mesenchymal stem cells would enable unproblematic and rapid availability of mesenchymal stem cells without the need of HLA typing.”

I am optimistic.  In a follow-up blog post, I will focus on research relating to one specific possible therapeutic role of MSCs – cartilage regeneration, an application for those who are suffering from lost cartilage in their knees, hips or elsewhere, a cure that can be done without need for surgery.  It works even if the patient has ongoing osteoarthritis which caused the problem in the first place.  I believe we are finally entering the new era of regenerative medicine. What incredible good news for longevity!