ESC v. iPSC: The difference is in efficiency

There are still a number of questions to consider when looking at using iPS in both regenerative medicine and disease modeling, as outlined previously. How similar are ES and iPS cells, can we mitigate the differences, and how much will these differences impact use of these cells? Two new papers this week address the first question (Feng et al., 2010; Hu et al., 2010); both groups directly compare ES and iPS cells looking at differences in differentiation, proliferation, and senecence. Their results boil down to few differences in the functional cells that are produced, but a vast decrease in the efficiency of iPS cells.

Feng et al. directly compared 14 hESC lines with 8 hiPSC lines, the latter generated by lentiviral Oct4, Sox2, Nanog, and Lin28 expresstion or retroviral Oct4, Sox2, Klf4 or c-Myc expression. All iPSC lines could be differentiated into hemangioblasts/blast cells, and hematopoietic and epithelial lineages, though with much lower efficiency than ESC lines (~500 fold). The iPSC-derived cells grew very slowly as compared to the ESC-derived cells, yielding significantly lower cell numbers (>1000 fold) and a higher percentage of senescent cells.

Hu et al. focused on neural differentiation. They compared 12 hiPSC lines (retroviral, lentiviral and non-integrated expression) with 5 hESC lines. All lines were able to differentiate into neuroepithelial cells using the same program, and the iPSC lines could be differentiated into both neurons and glia similarly to the ESC lines. Additionally, both groups could be differentiated to functional spinal motoneurons. However, the iPSC lines showed highly variable efficiency and differentiation, regardless of source or reprogramming method.

Regarding function, iPS cells have already been shown to be truly pluripotent, able to give rise to healthy adult mice via tetraploid complementation (Boland et al., 2009; Kang et al., 2009; Zhao et al., 2009); this work seems to support few functional or developmental differences between ES- or iPS-derived cells. The overwhelming issue remains to be the very low efficiency and variability of iPS cells to expand and differentiate. Hu et al. report this variability in cells of the same lines, derived from the same fibroblast, likely meaning that the cell of origin is not to blame. Is it the technique of reprogramming that triggers a senescent phenotype? Would other reprogramming methods (ie.with small molecules opposed to viral vectors) still result in this low efficiency? Furthermore, how much does this finding impact using iPS-derived neurons therapeutically? If the resulting neurons are functional, does this low efficiency matter (as long as we can generate enough cells)?

Bao-Yang Hu, Jason P. Weick, Junying Yu, Li-Xiang Ma, Xiao-Qing Zhang, James A. Thomson, and Su-Chun Zhang. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. PNAS published online before print February 16, 2010, doi:10.1073/pnas.0910012107