Taking stem cells to the clinic: Major challenges

Abstract

Stem cell therapy offers tremendous promise in the treatment of many incurable diseases. A variety of stem cell types are being studied but human embryonic stem cells (hESCs) appear to be the most versatile as they are pluripotent and can theoretically differentiate into all the tissues of the human body via the three primordial germ layers and the male and female germ lines. Currently, hESCs have been successfully converted in vitro into functional insulin secreting islets, cardiomyocytes, and neuronal cells and transfer of such cells into diabetic, ischaemic, and parkinsonian animal models respectively have shown successful engraftment. However, hESC-derived tissue application in the human is fraught with the problems of ethics, immunorejection, tumorigenesis from rogue undifferentiated hESCs, and inadequate cell numbers because of long population doubling times in hESCs. Human mesenchymal stem cells (hMSC) though not tumorigenic, also have their limitations of multipotency, immunorejection, and are currently confined to autologous transplantation with the genuine benefits in allogeneic settings not conclusively shown in large controlled human trials. Human Wharton's jelly stem cells (WJSC) from the umbilical cord matrix which are of epiblast origin and containing both hESC and hMSC markers appear to be less troublesome in not being an ethically controversial source, widely multipotent, not tumorigenic, maintain ''stemness'' for several serial passages and because of short population doubling time can be scaled up in large numbers. This report describes in detail the hurdles all these stem cell types have to overcome before stem cell-based therapy becomes a genuine reality.

Adapting Preclinical Benchmarks for First-in-Human Trials of Human Embryonic Stem Cell-Based Therapies

“…Compared with conventional small-molecule drugs, biologicals, and somatic cellular therapies, hESC-based interventions have unique characteristics that raise new quality, safety, and efficacy concerns in the transition from preclinical to clinical studies [8,10,12,41,44,45].…”

Stem cell bioprocess engineering towards cGMP production and clinical applications

“…by flow cytometry or proteomic analysis) (Bongso et al 2008;Baker et al 2007;Taylor et al 2011). For example, hESC-derived OPCs are characterized by a set of surrogate purity markers NG2, Nestin, and PDGFRa, as well as the impurity markers Tra-1-60 and Oct-4 for residual undifferentiated cells .…”

Immunogenicity and Immune-Modulating Properties of Human Stem Cells

“…Immunogenicity concerns represents a challenge of future stem cell therapy approaches (Drukker, 2004;Drukker & Benvenisty, 2004;Chidgey et al, 2008;Charron et al, 2009;Fairchild et al, 2004;2007). Ideally, the use of self stem cells would be the most encouraging path but many technical issues need to be solved before it can be brought to clinical practice (Ahrlund-Richter et al, 2009;Bongso et al, 2008;Chidgey et al, 2008;Ginty et al, 2011, Nehlin & Barington, 2009Yamanaka & Blau, 2010). Several strategies involved in sustaining antigen-specific tolerance through interplay between T reg and DC could prolong acceptance of hESC-derived tissues with minimal use of immunosuppressants (Lui et al, 2009;Lui et al, 2010).…”