Use of differentiated pluripotent stem cells in replacement therapy for treating disease

BACKGROUND Decades of laboratory and clinical investigation have led to successful therapies using hematopoietic stem cells (HSCs), but few other cell therapies have transitioned from experimental to standard clinical care. Providing patients with autologous rather than allogeneic HSCs reduces morbidity and mortality, and in some circumstances broader use could expand the range of conditions amenable to HSC transplantation. The availability of a homogeneous supply of mature blood cells would also be advantageous. An unlimited supply of pluripotent stem cells (PSCs) directed to various cell fates holds great promise as source material for cell transplantation and minimally invasive therapies to treat a variety of disorders. In this Review, we discuss past experience and challenges ahead and examine the extent to which hematopoietic stem cell transplantation and cell therapy for diabetes, liver disease, muscular dystrophies, neurodegenerative disorders, and heart disease would be affected by the availability of precisely differentiated PSCs. Unlimited populations of differentiated PSCs should facilitate blood therapies and hematopoietic stem cell transplantation, as well as the treatment of heart, pancreas, liver, muscle, and neurologic disorders. However, successful cell transplantation will require optimizing the best cell type and site for engraftment, overcoming limitations to cell migration and tissue integration, and possibly needing to control immunologic reactivity (challenges indicated in red). iPSC, induced PSC; ES cells, embryonic stem cells. Unlimited populations of differentiated PSCs should facilitate blood therapies and hematopoietic stem cell transplantation, as well as the treatment of heart, pancreas, liver, muscle, and neurologic disorders. However, successful cell transplantation will require optimizing the best cell type and site for engraftment, overcoming limitations to cell migration and tissue integration, and possibly needing to control immunologic reactivity (challenges indicated in red). iPSC, induced PSC; ES cells, embryonic stem cells. ADVANCES Although it is not yet possible to differentiate PSCs to cells with characteristics identical to those in the many organs that need replacement, it is likely a matter of time before these “engineering” problems can be overcome. Experience with cell therapies, both in the laboratory and the clinic, however, indicate that many challenges remain for treatment of diseases other than those involving the hematopoietic system. There are issues of immunity, separate from controlling graft rejection, and identifying the optimal cell type for treatment in the case of muscular dystrophies and heart disease. Optimization is also needed for the transplant site, as in diabetes, or when dealing with disruption of the extracellular matrix in treating degenerative diseases, such as chronic liver and heart disease. Finally, when the pathologic process is diffuse and migration of transplanted cells is limited, as is the case with Alzheimer’s disease, amyotrophic lateral sclerosis, and the muscular dystrophies, identifying the best means and location for cell delivery will require further study. OUTLOOK Considering the pace of progress in generating transplantable cells with a mature phenotype, and the availability of PSC-derived lineages in sufficient mass to treat some patients already, the challenges to scaling up production and eliminating cells with tumor-forming potential are probably within reach. However, generation of enough cells to treat an individual patient requires time for expansion, differentiation, selection, and testing to exclude contamination by tumorigenic precursors. Current methods are far too long and costly to address the treatment of acute organ injury or decompensated function. Immune rejection of engrafted cells, however, is likely to be overcome through transplantation of autologous cells from patient-derived PSCs. Availability of PSC-derived cell populations will have a dramatic effect on blood cell transfusion and the use of hematopoietic stem cell transplantation, and it will likely facilitate treatment of diabetes, some forms of liver disease and neurologic disorders, retinal diseases, and possibly heart disease. Close collaboration between scientists and clinicians—including surgeons and interventional radiologists—and between academia and industry will be critical to overcoming challenges and to bringing new therapies to patients in need. Challenges for stem cell–based therapies Patient-derived pluripotent stem cells (PSCs) hold promise in the treatment of injury and disease. An ever-increasing number of specific cell types can be generated from PSCs, but technical challenges remain in applying these cells in the clinic. Fox et al. review the challenges in attaining this goal. These include gene modification, cell rejection, and delivery and localization issues involved in transplantation of cells for the treatment of diabetes and disorders of the blood, liver, heart, and brain. Science, this issue 10.1126/science.1247391 Pluripotent stem cells (PSCs) directed to various cell fates holds promise as source material for treating numerous disorders. The availability of precisely differentiated PSC-derived cells will dramatically affect blood component and hematopoietic stem cell therapies and should facilitate treatment of diabetes, some forms of liver disease and neurologic disorders, retinal diseases, and possibly heart disease. Although an unlimited supply of specific cell types is needed, other barriers must be overcome. This review of the state of cell therapies highlights important challenges. Successful cell transplantation will require optimizing the best cell type and site for engraftment, overcoming limitations to cell migration and tissue integration, and occasionally needing to control immunologic reactivity, as well as a number of other challenges. Collaboration among scientists, clinicians, and industry is critical for generating new stem cell–based therapies.