Regulation of hematopoiesis from human pluripotent stem cells

 

Human pluripotent stem cells (PSC), whether hESC or iPSC, fail to generate definitive hematopoietic stem cells with multilineage and engraftment potential. By comparing lineage potential and proliferative capacity of CD34+ subsets generated from hPSC to those isolated from primary human hematopoietic sources, many groups have now defined key functional and transcriptional defects in PSC-derived cells. We identified the earliest stage of mesoderm commitment from hPSC (CD326-CD56+ embryonic mesoderm progenitors, aka EMP) (Evseenko et al, PNAS 2010), and demonstrated that gene regulatory programs necessary for development of definitive HSC are dysregulated during the initial stages of mesoderm differentiation, prior to hemato-endothelial commitment (Dravid et al, Molecular Therapy 2011). Studies by many groups including ours have provided proof of principle that hematopoiesis from PSC can be enhanced by constitutive over-expression of specific genes using lentiviral vectors. The challenge now is to understand how to best manipulate the intrinsic pathways and extrinsic signals during PSC differentiation to generate hematopoietic stem cells with normal self-renewal and lineage potential in a clinically relevant approach.