Abstract
Understanding the pathways guiding the development of definitive hematopoiesis with lymphoid potential is essential for advancing human pluripotent stem cell (hPSC) technologies for the treatment ofblood diseases and immunotherapies. In the embryo, lymphoid progenitors and hematopoietic stem cells (HSCs) arise from hemogenic endothelium (HE) lining arteries but not veins. Here, we show that activation of the arterial program through ETS1 overexpression or by modulating MAPK/ERK signaling pathways at the mesodermal stage of development dramatically enhanced the formation of arterial-type HE expressing DLL4 and CXCR4. Blood cells generated from arterial HE were more than 100-fold enriched in Tcell precursor frequency and possessed the capacity to produce B lymphocytes and red blood cells expressing high levels of BCL11a and β-globin. Together, these findings provide an innovative strategy to aid in the generation of definitive lymphomyeloid progenitors and lymphoid cells from hPSCs for immunotherapy through enhancing arterial programming of HE.
Highlights
De novo production of hematopoietic and lymphoid cells from in vitro-expandable human cells, such as human pluripotent stem cells represents a promising approach for transplantation and immunotherapies of hematologic diseases and cancers
ETS1 Induction Upregulates SOXF and NOTCH Signaling-Associated Genes and Enhances Arterial Specification In the embryo, arterial fate is specified following induction of DLL4 expression (Chong et al, 2011), initiated by signaling through an artery-specific enhancer located within the third intron of DLL4 that is controlled by ETS factors (Sacilotto et al, 2013; Wythe et al, 2013)
We treated cultures with DOX beginning at the mesodermal stage of development and analyzed the expression of the arterial markers DLL4 and CXCR4 (Chong et al, 2011; Yamamizu et al, 2010) on CD144+ (VE-cadherin+) endothelial cells emerging on day 4 of differentiation (Figure 1A)
Summary
Understanding the pathways guiding the development of definitive hematopoiesis with lymphoid potential is essential for advancing human pluripotent stem cell (hPSC) technologies for the treatment of blood diseases and immunotherapies. Blood cells generated from arterial HE were more than 100-fold enriched in T cell precursor frequency and possessed the capacity to produce B lymphocytes and red blood cells expressing high levels of BCL11a and b-globin. Together, these findings provide an innovative strategy to aid in the generation of definitive lymphomyeloid progenitors and lymphoid cells from hPSCs for immunotherapy through enhancing arterial programming of HE
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call