The safety of human pluripotent stem cells in clinical treatment

Figures & data

Table I. Properties of hPSC types developed using presently existing technologies.

hPSC type	Patient-specific cell lines that prevent alloimmune response	Lack of epigenetic aberrations	Reported methods for derivation under xeno-free and chemically defined conditions	Ongoing clinical trials
hESCs	–	+	+	+
iPSCs	+	– ^a	+	+
NT-ESCs	–/+ ^b	+/–	–	–
phESC	+	–	–	–

^aEpigenetic imperfections of human iPSCs tend to subdue with time, but prolonged culturing of hPSCs in vitro leads to adaptive genetic changes that may show similarity to those found in tumors.

^bHuman NT-ESCs are HLA-matched with the donor of the somatic cell, but allogeneic mitochondria, which mainly originate from the oocyte, may trigger an adaptive alloimmune response.

Figure 1. Schematic representation of hPSCs generation methods. A: Derivation of hESCs from inner cell masses of blastocysts or from single blastomeres. The latter method allows derivation of hESC lines without destruction of human embryos. B: Generation of nuclear transfer embryonic stems cells (NT-ESCs) using somatic cell nuclear transfer into an enucleated human oocyte. C: Generation of induced pluripotent stem cells (iPSCs) using ectopic expression or direct delivery of certain mRNAs or proteins in somatic cells. Earlier methods used Lenti- and Adenoviruses for the ectopic expression (shown in grey) that integrate into the host genome creating genetic mutations. Therefore, such cells cannot be used in human therapies for safety reasons. Integration-free human iPSCs are generated using Sendai virus, direct delivery of mRNAs, proteins, or small molecules. D: Generation of parthenogenetic human embryonic stem cells (phESCs). Depending on the oocyte activation protocol, the resulting phESCs may be heterozygous or homozygous for human leukocyte antigens (HLAs).

Table II. Ongoing clinical trials involving hPSCs with enrolled patients.

Clinical trial number ^a (condition)	hPSC type	Phase	The study designed to test for	Country/start date	Number of patients enrolled	Published results
NCT01217008 (Spinal cord injury)	hESCs	1	Safety	USA / 2010 Oct	4 or 5	No
NCT01345006 (Stargardt's macular dystrophy); NCT01344993 (Age-related macular dystrophy)	hESCs	1/2	Safety and efficacy	USA / 2011 Apr	18	Schwartz et al., Lancet, 2014
? ^b	hiPSCs	? ^b	? ^b	Japan / 2014 Sept	1	No
NCT02239354 (Type I diabetes mellitus)	hESCs	1/2	Safety and efficacy (change in C-peptide expression level)	USA / 2014 Nov	40	No

^aSee ClinicalTrials.gov.

^bThe Japanese study has not been registered in ClinicalTrials.gov, and available information about it is very sketchy.