Renewed Interest in Regenerative Medicine

On November 16, 2017, the US FDA announced a comprehensive policy framework for the development and oversight of regenerative medicine products, including novel cellular therapies. This risk-based framework includes a suite of guidance documents focusing on safety and effectiveness of these therapies, and reiterates FDA’s commitment to bring new effective therapies to patients as quickly and safely as possible. The origin of regenerative medicine can be traced back more than half a century ago to the first successful human organ transplantation. Unlike lower vertebrates such as zebrafish and amphibians, humans cannot regenerate organs (except the liver), and organ transplantation has been the cornerstone therapy to replace diseased ormalfunctioning ones. Major stumbling blocks with organ transplantation include the lack of donors and that recipients often need to be HLA-matched and/ or immunosuppressed to avoid transplant rejection. Despite the lack of regenerative capacity, most human organs can repair themselves upon injuries, and this tissue healing process serves as the principle of regenerative medicine. Since their discovery more than three decades ago, stem cells have been at the heart of regenerative medicine development thanks to their ability to self-renew and differentiate into a variety of cell lineages. Stem cell transplantation has been used successfully in several human diseases,most notably in hematological cancers such as leukemia. However, stem cell therapy has not yet achieved the level of solid organ regeneration. Let us take the heart as an example. We have learned a lot about the heart’s regenerative mechanism from animal models such as zebrafish and neonatal mice. But in humans and non-human primates, once the heart has fully developed, it cannot regenerate large areas of damage such as those that might arise after a heart attack, although it can heal minor injuries through scar formation. There have been several stem cell-based Phase 1/2 clinical trials for heart diseases, primarily aimed at evaluating safety and improvement in cardiac functions, with the majority involving autologous mesenchymal stem cells for heart failure. The quality of autologous stem cells greatly depends on the patient’s age and health status. Allogeneic stem cells from young and healthy donors are an alternative, but this requires careful HLAmatching and often immunosuppression to avoid serious side effects such as graft-versus-host disease. No stem cell therapy for heart diseases has reached regulatory approval stage. Progress has been hampered, in part, because we don’t yet fully understand the underlying mechanisms of how best to regenerate heart tissue from progenitor cells. Stem cells come in different flavors: cardiac progenitor cells, bone marrow-derived mesenchymal stem cells, hematopoietic stem cells, endothelial progenitor cells–and one question in the field is which “flavor” will achieve the best outcome for heart regeneration?