Ethical and Safety Issues of Stem Cell-Based Therapy

Abstract

Results obtained from completed and on-going clinical studies indicate huge therapeutic potential of stem cell-based therapy in the treatment of degenerative, autoimmune and genetic disorders. However, clinical application of stem cells raises numerous ethical and safety concerns. In this review, we provide an overview of the most important ethical issues in stem cell therapy, as a contribution to the controversial debate about their clinical usage in regenerative and transplantation medicine. We describe ethical challenges regarding human embryonic stem cell (hESC) research, emphasizing that ethical dilemma involving the destruction of a human embryo is a major factor that may have limited the development of hESC-based clinical therapies. With previous derivation of induced pluripotent stem cells (iPSCs) this problem has been overcome, however current perspectives regarding clinical translation of iPSCs still remain. Unlimited differentiation potential of iPSCs which can be used in human reproductive cloning, as a risk for generation of genetically engineered human embryos and human-animal chimeras, is major ethical issue, while undesired differentiation and malignant transformation are major safety issues. Although clinical application of mesenchymal stem cells (MSCs) has shown beneficial effects in the therapy of autoimmune and chronic inflammatory diseases, the ability to promote tumor growth and metastasis and overestimated therapeutic potential of MSCs still provide concerns for the field of regenerative medicine. This review offers stem cell scientists, clinicians and patient's useful information and could be used as a starting point for more in-depth analysis of ethical and safety issues related to clinical application of stem cells.

Keywords: embryonic stem cells; induced pluripotent stem cells; mesenchymal stem cells; stem cell-based therapy..

Figure 1

Schematic diagram describing characteristics of ESCs. Embryonic stem cells (ESCs) are harvested from a blastocyst. Embryonic stem (ES) cells are derived from the inner cell mass of the pre-implantation embryo. Fully characterized hESCs express typical pluripotent stem cell markers such as octamer-binding transcription factor 3/4 (OCT3/4), stage specific embryonic antigens 3 and 4 (SSEA-3 and SSEA-4), TRA-1-60, and TRA-1-81.These cells are pluripotent, meaning they can differentiate into cells from all three germ layers (ectoderm, mesoderm and endoderm). Main ethical issues (labeled with question marks): isolation of ESCs involves the destruction of a human embryo; transplantation of undifferentiated ESCs may result with a formation of teratomas, tumors that contain all three germ layers.

Figure 2

Potential applications of human induced pluripotent stem cells (iPSCs). iPSC technology can be potentially utilized in disease modeling, drug discovery, gene therapy, and cell replacement therapy. Genetic mutations can be corrected by gene targeting approaches before or after reprogramming. iPSCs are considered morally superior then ESCs since their generation do not require destruction of embryos. Introduction of the four transcription factors-“Yamanaka factors“ (Oct-4, Sox-2, Klf-4, and c-Myc) leads to reprogramming of a somatic cell to an iPSC which can further differentiate into different types of cells. Two types of methods for the delivery of reprogramming factors into the somatic cells can be used: integrating viral vector systems and non-integrating methods. The main safety issue regarding iPSC-based therapy (labeled with question marks) is the risk of teratoma formation which might happen if patient receive iPSC-derived cells that contain undifferentiated iPSC and dilemma whether retroviral and lentiviral-free iPSC are safe for clinical application.

Figure 3

Differentiation ability and immune-modulatory characteristics of MSCs. MSCs are adult, fibroblast-like, multipotent cells, most frequently isolated from bone marrow (BM), adipose tissue (AT) and umbilical cord blood (UCB). Minimal criteria for characterization of MSCs are: cell surface expression of CD105, CD73, CD90 and the absence of hematopoietic markers CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR. MSCs have been applied clinically in patients with inflammatory bowel diseases (IBD), liver disorders and cardiac diseases with very encouraging results. MSCs possess broad spectrum of immuno-modulatory capacities. Serious adverse events noticed in some of MSC-treated patients could be explained by the fact that MSCs either suppress or promote inflammation in dependence of inflammatory environment to which they are exposed to. The primary concerns for clinical application of MSCs (labeled with question marks) are unwanted differentiation of the transplanted MSCs and their potential to suppress anti-tumor immune response and generate new blood vessels that may promote tumor growth and metastasis.