Engineering the haemogenic niche mitigates endogenous inhibitory signals and controls pluripotent stem cell-derived blood emergence

Nafees Rahman, Patrick M. Brauer, Lilian Ho, Tatiana Usenko, Mukul Tewary, Juan Carlos Zúñiga-Pflücker and Peter W. Zandstra ()
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Nafees Rahman: University of Toronto
Patrick M. Brauer: Biological Sciences, Sunnybrook Research Institute
Lilian Ho: Life Sciences (Biochemistry), University of Waterloo
Tatiana Usenko: Institute of Biomaterials and Biomedical Engineering, University of Toronto
Mukul Tewary: Institute of Biomaterials and Biomedical Engineering, University of Toronto
Juan Carlos Zúñiga-Pflücker: Biological Sciences, Sunnybrook Research Institute
Peter W. Zandstra: University of Toronto

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Efforts to recapitulate haematopoiesis, a process guided by spatial and temporal inductive signals, to generate haematopoietic progenitors from human pluripotent stem cells (hPSCs) have focused primarily on exogenous signalling pathway activation or inhibition. Here we show haemogenic niches can be engineered using microfabrication strategies by micropatterning hPSC-derived haemogenic endothelial (HE) cells into spatially-organized, size-controlled colonies. CD34+VECAD+ HE cells were generated with multi-lineage potential in serum-free conditions and cultured as size-specific haemogenic niches that displayed enhanced blood cell induction over non-micropatterned cultures. Intra-colony analysis revealed radial organization of CD34 and VECAD expression levels, with CD45+ blood cells emerging primarily from the colony centroid area. We identify the induced interferon gamma protein (IP-10)/p-38 MAPK signalling pathway as the mechanism for haematopoietic inhibition in our culture system. Our results highlight the role of spatial organization in hPSC-derived blood generation, and provide a quantitative platform for interrogating molecular pathways that regulate human haematopoiesis.

Date: 2017
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DOI: 10.1038/ncomms15380

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