Challenges to the clinical application of pluripotent stem cells: towards genomic and functional stability

Abstract

Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and are pluripotent, retaining the ability to differentiate into all cell types in the body. As a renewable source of various types of human cells, hESCs hold great therapeutic potential. Although significant advances have been achieved in defining the conditions needed to differentiate hESCs into various types of biologically active cells, many challenges remain in the clinical development of hESC-based cell therapy, such as the immune rejection of allogeneic hESC-derived cells by recipients. Breakthroughs in the generation of induced pluripotent stem cells (iPSCs), which are reprogrammed from somatic cells with defined factors, raise the hope that autologous cells derived from patient-specific iPSCs can be transplanted without immune rejection. However, recent genomic studies have revealed epigenetic and genetic abnormalities associated with induced pluripotency, a risk of teratomas, and immunogenicity of some iPSC derivatives. These findings have raised safety concerns for iPSC-based therapy. Here, we review recent advances in understanding the genomic and functional stability of human pluripotent stem cells, current challenges to their clinical application and the progress that has been made to overcome these challenges.

Keywords: Embryonic stem cells; cell therapy; epigenetics; genetic stability; immune rejection; induced pluripotent stem cells.

Figure 1

p53 maintains genetic stability of ESCs by coordinating their DNA damage response and self-renewal. The activation of p53 in ESCs by oncogenic and genotoxic stresses could lead to activation of the G2/M checkpoint and apoptosis of ESCs. In addition, p53 suppresses the expression of the pluripotency factor NANOG, thus maintaining the genetic stability of ESCs in the self-renewing pool by eliminating DNA-damaged ESCs.

Figure 2

p53 suppresses induced pluripotency. p53 is activated by multiple stimuli in cells undergoing reprogramming, including the oncogenic potential of the reprogramming factors, reprogramming-induced oxidative stress and DNA double-stranded breaks (DSBs), and telomere shortening, which can ultimately block successful iPSC production. Therefore, the transient or partial inactivation of p53 might be required for cells undergoing reprogramming to complete their dedifferentiation into iPSCs, but this might also provide a window of opportunity for the accumulation of genetic abnormalities.

Figure 3

The interaction between the ESC/iPSC-derived cells and T cells in recipients. In addition to the engagement of the T-cell receptor (TCR) and the allogeneic or syngeneic major histocompatibility complex (MHC) containing self- or foreign peptides on the surface of ESC- or iPSC-derived cells, secondary activation pathways such as those involving the interaction of CD28 with B7 and CD40 with CD40L are also critical for T-cell activation. CTLA4 has higher binding affinity for CD28 and can effectively block the interaction between B7 and CD28, leading to the inhibition of T-cell activation.