16.02.10
Induced pluripotent stem cells not appropriate to study disease mechanims
Madison – Human induced pluripotent stem cells (hiPSC) differentiate less efficiently than human embryonic stem cells (hESC) and develop into functional neurons in highly variable amounts. Consequently, they may be not appropriate to investigate human disease mechanisms, according to a new study published in PNAS (doi: 10.1073/pnas.0910012107). Su-Chun Zhang and colleagues from Waisman Center in Madison found that 12 hiPSC lines and 5 HESC lines appeared almost indistinguishable with regard to their morphology, transcriptome and developmental time course, when differentiated to neuroepithlial cells using a standardised protocol. But while various hESC lines differentiated into neuroepithelial progenitor cells at a similar efficiency under defined adherent colony culture, hiPSC demonstrated significant variability, independant of the presence or absence of certain reprogramming factors or the reprogramming method used. While all hESC lines yielded 90-97% of PAX-6-expressing neuroepithelial cells after 15 days of in-vitro culture, hiPSCs reprogrammed with lentiviral methods exhibited lower and variable neural differentiation (15-79%) regardless of the origin of fibroblasts from which they were derived. Similarly, two retrovirally induced iPSCs showed less efficient neural differentiation (15%) and furthermore, use of non-integrating episomal vectors did not alter differentiation efficacy and reproducibility. hiPSCs do not faithfully mirror all the differentiation capabilities of hESCs, according to the researchers. This suggests that there are unknown factors in play that may limit the use of induced cells use in terms of modelling disease in the laboratory, one of the most important potential applications suggested for hiPSCs. Such unknowns would also limit their applicability in clinical settings such as for cell therapies. The researchers believe that progenies of hiPSCs might be epigentically unique and predisposed to generate cells of a particular sublineage. The results of the systematic comparison of hESCs and hiPSCs suggest that hiPSCs seem to respond differently to extracellular factors and are suitable for applications that require the generation of particular cell types. “The results tells us the techniques for generating ipSCs are still not optimal“ says Zhang. “There is room for improvement.“