Pluripotent Stem Cells into Somatic Cells(New source for hematopoietic lineage)
  • Jong-Hee Lee Ph.D
  • SLS Colloquia / March 21st 04L00 pm / Bldg.110 Room N104
Abstract

Human pluripotent stem cells (hPSCs) have the unique capacity to give rise to all cell types of the body and provide an invaluable source for regenerative medicine. Thus, hPSCs have been suggested as an alternative source of cells for hematopoietic cell-based therapies, instead of adult sources such as umbilical cord blood (UCB), bone marrow and mobilized peripheral blood, for in vivo reconstitution of the hematopoietic system, but are limited by proficient lineage-specific differentiation. Efficient and controlled differentiation to specific lineages represents the major barrier for future clinical applications of hPSCs, including cell replacement therapies and drug discovery. Therefore, a deeper understanding of the starting populations of hiPSCs is required to instruct proficient differentiation. Our study demonstrates that although the hiPSC lines express pluripotent genes and support differentiation into cell types of all three germ layers, measured by established assays for pluripotency, hiPSC lines possess unique functional properties when induced to differentiate, where these distinct properties are predetermined at the transcriptome level of undifferentiated hiPSC states. We also demonstrates reduction of Hedgehog (Hh) signaling correlates to developmental progression of hematopoiesis throughout human ontogeny. Our results reveal an unprecedented role for Hh signaling in the regulation of adult hematopoietic specification, thereby demonstrating the ability to modulate the default embryonic programs of hPSCs.

We also present that the naive state enhances self-renewal while restricting lineage differentiation in vitro to neural default fate. Molecular analyses indicate expression of multiple lineage-associated transcripts in naive hPSCs that failed to predict biased functional differentiation capacity. Suppression of OCT4 but not NANOG allows immediate recovery directly from naive state. Our study reveals unique cell-fate restrictions in human pluripotent states and provides an approach to overcome these barriers that harness both efficient naive hPSC growth while maintaining in vitro differentiation essential for hPSC applications.

Induced pluripotent stem cell reprogramming has provided critical insights into disease processes by modeling the genetics and related clinical pathophysiology. Human cancer represents highly diverse genetics, as well as inter- and intra-patient heterogeneity, where cellular model systems capable of capturing this disease complexity would be invaluable. We report our efforts to induce pluripotency from the heterogeneous population of human patients that represents this disease in the clinic. Using robust optimized reprogramming methods, we demonstrate that reprogramming of AML cells harboring leukemic genomic aberrations is a rare event with the exception of those with de novo mixed-lineage leukemia (MLL) mutations that can be reprogrammed and model drug responses in vitro.