Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Yi-Fen Lu, Patrick Cahan, Samantha Ross, Julie Sahalie, Patricia M. Sousa, Brandon K. Hadland, Wenqing Cai, Erik Serrao, Alan N. Engelman, Irwin D. Bernstein, George Q. Daley
Hematopoietic stem cell (HSC) transplantation is curative for malignant and genetic blood disorders, but is limited by donor availability and immune-mismatch. Deriving HSCs from patient-matched embryonic/induced-pluripotent stem cells (ESCs/iPSCs) could address these limitations. Prior efforts in murine models exploited ectopic HoxB4 expression to drive self-renewal and enable multi-lineage reconstitution, yet fell short in delivering robust lymphoid engraftment. Here, by titrating exposure of HoxB4-ESC-HSC to Notch ligands, we report derivation of engineered HSCs that self-renew, repopulate multi-lineage hematopoiesis in primary and secondary engrafted mice, and endow adaptive immunity in immune-deficient recipients. Single-cell analysis shows that following engraftment in the bone marrow niche, these engineered HSCs further specify to a hybrid cell type, in which distinct gene regulatory networks of hematopoietic stem/progenitors and differentiated hematopoietic lineages are co-expressed. Our work demonstrates engineering of fully functional HSCs via modulation of genetic programs that govern self-renewal and lineage priming.

Graphical abstract

Teaser

Embryonic/induced pluripotent stem cells (ESCs/iPSCs) represent an unlimited source of hematopoietic stem cells (HSCs) for treating blood diseases. By modulating genetic programs governing self-renewal and lineage-guiding pathways, Lu et al. derive engineered HSCs with robust lymphoid potential and endow adaptive immunity in vivo.


http://ift.tt/2iiphD4