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.
