Stem cell therapy has the potential to treat a myriad of diseases that have limited options for cure. Challenges, however, still remain before cell based therapy can be used routinely to treat disorders of the heart, nervous system, and pancreas. An ongoing debate is the identification of the most optimal cell type. The advantage of using hESCs is their ability to self-renew and to differentiate into any cell; thus, these cells can potentially regenerate the entire organ. Their disadvantage is a potential for immunologic rejection and need for immunosuppressive therapy. Use of cells from embryos has also met with several regulatory hurdles. Only recently has the FDA approved the first Phase 1 clinical trial using hESCs for the neural regeneration in patients with severe spinal cord injury.
Adult progenitor cells, on the other hand, are limited to differentiating into cell types from the tissue of origin. Adult progenitor cells are rare in mature organs and can be difficult to expand in culture. However, they are considered less immunogenic than hESCs and their therapeutic application has been less controversial. Thus, the majority of clinical trials have used adult progenitor cells. Results, however, have been mixed, leading many to question their regeneration potential and ability to differentiate, survive and engraft (29
Some of these challenges can be addressed by using iPSCs. iPSCs are derived from the patients’ adult cells; thus, there is an unlimited supply and rejection is not an issue. These cells can be cultured, expanded and differentiated in vitro
and transplanted into injured tissue. However, the efficiency of reprogramming and differentiation remains low. Whether these cells truly differentiate into target tissue or retain some features of their tissue of origin has also been questioned (80
). Finally, efficient derivation of iPSCs still require viral transfection for reprogramming, presenting obstacles for regulatory approval. A clinical trial has not been yet been initiated using iPSCs.
For the heart, challenges facing stem cell therapy involve each step of treatment, from cell isolation to long-term safety (82
). For example, determining the sufficient cell number and the mode of cell delivery remain unclear. In addition, survival and proliferation in the inflammatory environment of the infarcted myocardium has been challenging as >90% of cells die within a week. Addressing this issue will require better understanding of the acute donor cell death phenomenon. Electromechanical integration of cells is also required for improvement of cardiac function. Transplanted cells must have long-term electromechanical stability to prevent the development of dangerous arrhythmias. Currently, these challenges have not been adequately met as most clinical studies have focused on the safety of the transplantation procedure and the improvement in LV systolic function or perfusion after stem cell therapy.
The application of stem cells for neurological disorders may be even more complex than other diseases (83
). Stem cells need to integrate into a sophisticated system of interconnected cells that extend over great distances, which may be challenging in the absence of stimuli to guide the development of neural networks. In addition to the poor survival rate, transplanted cells are also subject to the same progressive and recurrent pathological processes that caused the initial neurological injury, making it necessary to implant large grafts. Controlling stem cell proliferation and differentiation into appropriate cellular phenotypes is also necessary for organ specific function and to prevent tumor formation. Finally, it is unclear whether findings in animal models can translate into human studies because of the differences in species plasticity and an incomplete understanding of disease processes. In Parkinson’s disease (83
), for example, there has not yet been a clear demonstration that neurons generated in vitro
can efficiently reinnervate the striatum, release dopamine in vivo,
or result in functional recovery from deficits resembling human symptoms, despite promising results in preclinical studies.
For treatment of diabetes, a recent study has demonstrated the potential of autologous non-myeloablative hematopoietic stem cell transplantation; however, almost half the patients had adverse effects associated with the procedure, including late endocrine dysfunction, autoimmune polyendocrine syndrome, and cyclophosphamide-related oligospermia (79
). The use of hESCs or iPSCs may minimize these complications, but early protocols have failed to generate functional β-islet cells. More recently, protocols, which included all stages of β-cell development, have successfully produced glucose-responsive insulin secreting cells in vivo
). Although promising, communication between transplanted cells and different islet cells and the extracellular matrix, which together provide normal glycemic control, has not yet been demonstrated. The function, survival, and replication of these cells ultimately rely on their ability to exist in the highly specialized microenvironment of the islet (2
). Finally, replacement of the cells does not address the cause for disease, which not only destroys native cells but also transplanted cells (2
). Specifically, in the case of Type I diabetes, autoimmune antibodies can also destroy stem cells, leading to the need for repeat transplantations.
Although the future for patients with heretofore incurable diseases of the heart, nervous system, and pancreas appears brighter with the advent of stem cell based therapy, more research is needed before stem cells can effectively repair damaged tissue. By performing a complete evaluation of the stem cell lineage, fate, and function in preclinical and clinical trials, we will ensure that one day patients will routinely receive this novel therapy.