The promise of MSCs

Carolyn Peluso, Ph.D.

 

In 2009, Charla Nash was the victim of a brutal animal mauling that left her without hands and with a face mutilated beyond recognition. Two years later, doctors attempted a face and hand transplant that took a surgical team 20 hours to perform. Sadly, the hand transplants failed almost immediately and had to be removed, but the face transplant succeeded, dramatically improving her quality of life. Her transplant was met with excitement from the medical establishment and the general community, which prompted invitations to appear on Oprah and the Today Show. Her transplant was considered something of a medical marvel and in fact, successful transplants of this kind (also known as a composite tissue allograph or CTA) are something of a rare bird. The first successful hand transplant occurred in 1998 and since then only about 200 patients have undergone the procedure worldwide¹ and with only limited success.  The rarity and poor success rate seems especially low when one considers that 28,000 patients undergo solid organ transplantations (e.g., heart, liver, kidney) with significant success in the just the US every year (United Network for Organ Sharing at www.UNOS.org).

In contrast to solid organ transplants, however, CTAs require the integration of multiple tissue types (i.e., muscle, fat, nerve, and highly-antigenic skin). The complexity of the transplant and the antigenicity of the skin tissue make rejection more likely than solid organ transplants¹. As a result, CTA patients are tied to the same onerous life-long burden of immunosuppressive therapy that solid organ recipients face, but in addition they face an increased risk of rejection complications.  Taking on the transplantation risks make sense for solid organ recipients who cannot survive without the transplant, but CTA recipients are generally healthy, aside from the missing limb². Thus, the procedure is about quality of life, not life-or-death, and the decision to proceed has to be balanced against the dangers of immunosuppressive therapy and rejection complications. Therefore, physicians need a way to reduce the immunological dangers of the CTA in order to offer it to patients on a wider scale; and this is where Mesenchymal Stem Cells (MSCs) may come into play.

MSCs are stromal cells that exist in tissues, such as the bone marrow and adipose and that can differentiate down multiple mesenchymal lineages (i.e., chrodrocytes, osteoblasts, adipocytes). This feature of MSCs has been successfully exploited to facilitate tissue reconstruction in orthopedic procedures³. In addition to their tissue regenerative capacity, however, MSCs exert important influence on both innate and adaptive immunity. For example, MSCs are able to affect innate immune function through various channels that include inhibiting the antigen-presenting function of dendritic cells, regulating HLA-G expression to block Natural Killer cell activity, and down-regulating IFN-g expression⁴. At the same time, MSCs affect adaptive immunity in part by mediating the nitric oxide system, and the expression of cytokines and growth factors⁴.  Clinically, the capacity of MSCs to affect the immune response in the transplant environment has been demonstrated in several studies. One of which, showed, using a randomized kidney transplant trial, that treatment with MSCs lowers the incidence of acute rejection, and opportunistic infection when compared to other immune-modulating therapies (i.e., anti-IL-2 antibodies)^{4, 5}.

Currently, researchers are applying the lessons learned by the solid organ transplant community to the specialized problems of the CTA procedure. For example, investigators need to establish a culture paradigm that optimizes the immune-modulatory potential of the cells, so they can overcome the high antigenicity of the skin graft component of the CTA – a problem not shared by the solid organ transplant community. To this end, researchers have shown in rat and primate models that treatment with MSCs can increase the survival time of skin grafts, although immunosuppression was still necessary and the rate of long-term tolerance was poor⁴. It’s a good first step, but there are still a lot of unanswered questions.  Investigators will need to develop an appropriate method of MSCs application, and they will need to understand how immunosuppressive drugs and MSCs interact so they can limit the negative influence of the former and improve the effectiveness of the later. The path is long, but the goal is in clear sight, and investigators are in active pursuit. It is exciting to think that someday, in the not so distant future, people like Charla Nash will be able to overcome life-altering tissue injuries in a common-place way, without being considered a medical marvel, thanks to MSCs.

1.            Schnider, JT et al. Site-specific immunosuppression in vascularized composite allotransplantation: prospects and potential. Clin Dev Immunol 2013, 495212 (2013).

2.            Antony, AK et al. Composite tissue allotransplantation and dysregulation in tissue repair and regeneration: a role for mesenchymal stem cells. Front Immunol 4, 188 (2013).

3.            Steinert, AF, Rackwitz, L, Gilbert, F, Noth, U & Tuan, RS. Concise review: the clinical application of mesenchymal stem cells for musculoskeletal regeneration: current status and perspectives. Stem Cells Transl Med 1, 237-47 (2012).

4.            Plock, JA, Schnider, JT, Solari, MG, Zheng, XX & Gorantla, VS. Perspectives on the use of mesenchymal stem cells in vascularized composite allotransplantation. Front Immunol 4, 175 (2013).

5.            Tan, J et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 307, 1169-77 (2012).