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Directed Differentiation and Lineage Conversion

LineageThe discovery of iPS technology in 2006 (Takahashi and Yamanaka, 2006) opened the door for possible application of pluripotent stem-cell related therapies in the clinic as well as for the generation of patient-derived pluripotent stem cells suitable for disease modeling in vitro. Maintenance of somatic cell epigenetic marks during reprogramming implies that different iPSC lines might bear bias differentiation potential. Furthermore, and regardless of the methodology used for reprogramming, the lack of robust and efficient differentiation protocols may lead, not only mixed populations, but most importantly, to residual pluripotent stem cells that can cause tumor formation upon transplantation. Our goal is to define and develop robust protocols of differentiation displaying minimal differences between pluripotent lines as well as to reduce contamination with undifferentiated cells.

1. Will the use of highly-pure iPS differentiated cell populations generate tumors in vivo?

Considering the risk for tumor formation upon transplantation of residual pluripotent cells, we are investigating whether the combination of high-efficient differentiation methods alongside positive and/or negative selection can result in tumorigenesis upon transplantation.

2. Can epigenetic memory be erased?

Epigenetic memory has been observed at the pluripotent state, however it is still unknown how epigenetic marks fluctuate not only during directed differentiation of pluripotent cells but also during lineage conversion processes. We aim to develop technologies at the single cell level that might contribute to our understanding of the molecular mechanisms controlling the epigenome.

3. Can the pluripotent state be bypassed in favor of partial induction of potency followed by directed differentiation into the cell types of interest?

By combining our knowledge on development, differentiation and stem cell biology, our laboratory is currently developing strategies for the direct lineage conversion of somatic cells into a number of different cell-types in parallel to the directed differentiation from pluripotent cells. Ultimately, we aim to generate a battery of methodologies allowing for the rapid and safe generation of specific cell-types suitable for clinical translation.