The scientific community has held tremendous hope for the eventual emergence of stem cell transplantation as a broadly applicable and highly effective therapeutic strategy. However, the realization of this hope has been plagued by the indomitable immune response to the transplantation of human embryonic stem cell (hESC) derivatives, which prevents the engraftment and long-term survival necessary for functional recovery or preservation of the host tissue.
In an article featured in the latest issue of STEM CELLS, a research group from Stanford University describes a novel regimen for quashing this immunologic barrier – a short-course treatment with two costimlation-adhesion blockade agents, allowing engraftment of transplanted differentiated stem cells and their prolonged survival in tissue.
“Inducing immune tolerance to human embryonic stem cell graft is critical for the clinical success of regenerative medicine,” commented Dr. Joseph Wu, M.D., Professor of Medicine and Radiology at the Stanford University School of Medicine. “We have realized, however, that traditional immunosuppressive therapies used to prevent solid organ rejection, such as calcineurin inhibitors and corticosteroids, are insufficient to prevent human embryonic stem cell rejection following transplantation.”
In the study, hESCs were made to express enhanced green fluorescent protein (eGFP), differentiated to endothelial cells and cardiomyocytes, and transplanted into mouse hindlimbs as well as into both healthy and ischemic mouse myocardia. A novel costimulation-adhesion blockade method was then used alongside a more traditional therapy involving cyclosporine to induce immunosuppression. Detection of eGFP in the tissues allowed the team to track the engraftment and longevity of the transplanted cells over time. The costimulation-adhesion method yielded vastly superior results to the cyclosporine treatment, not only showing significantly improved engraftment and survival of the cells in the tissues but ultimately showing the effective preservation of cardiac function following stem cell transplantation in an induced myocardial infarction model, as shown through MRI.
“Here we demonstrate that a short-course, dual-agent regimen that prevents optimal T cell activation is sufficient to promote the robust and long-term survival of embryonic stem cell derivatives in both healthy and injured tissues in mouse models,” Dr. Wu explained. The authors indicate that the superior response of the transplanted cells to the costimulation-adhesion therapy may be attributed to its repression of both adaptive and innate immunity, which is likely to aid in mitigating the tissues’ rejection of these characteristically immunogenic cells. The researchers’ method led to both local and systemic upregulation of T cell immunoglobulin and mucin domain 3 (TIM3), a Th-1-specific cell surface protein, in addition to an overall reduction of pro-inflammatory cytokines.
“Application of hESC and iPSC-derived cells holds great promise for cell replacement therapies in man, with clinical trials already ongoing in USA/Europe and soon in Japan,” noted Majlinda Lako, Ph.D., Associate Editor for STEM CELLS and Professor of Stem Cell Science at the Institute of Genetic Medicine, Newcastle University. “This current study brings us a step closer to overcoming immunological barriers that have hampered these clinical promises and addresses important issues that must be tackled before successful realization of pluripotent stem cell therapies can take place in humans.”
Speaking on behalf of his research team, Dr. Wu stated, “We are excited by these findings and about their implications for the field. This work demonstrates a simple, effective approach to overcome the immunologic barrier of using human embryonic stem cell derivatives that is far superior to conventional agents currently in use clinically.”