TY - JOUR
T1 - Identification of a retinoic acid-dependent haemogenic endothelial progenitor from human pluripotent stem cells
AU - Luff, Stephanie A.
AU - Creamer, J. Philip
AU - Valsoni, Sara
AU - Dege, Carissa
AU - Scarfò, Rebecca
AU - Dacunto, Analisa
AU - Cascione, Sara
AU - Randolph, Lauren N.
AU - Cavalca, Eleonora
AU - Merelli, Ivan
AU - Morris, Samantha A.
AU - Ditadi, Andrea
AU - Sturgeon, Christopher M.
N1 - Funding Information:
S.A.L., C.D. and J.P.C. received support from an NHLBI T32 Training Grant (HL007088-41). S.M. is supported by a Vallee Scholar Award and an Allen Distinguished Investigator Award. A.D. is supported by the Telethon Foundation (TIGET grants nos. C4 and G3b) and San Raffaele Hospital (Seed Grant). C.M.S. is supported by an American Society of Hematology Scholar Award, an American Society of Hematology Bridge Grant, a Washington University Center of Regenerative Medicine Pilot Grant, the Bill & Melinda Gates Foundation INV-002414, and NIH R01HL145290 and R01HL151777. This publication was made possible, in part, by grant no. UL1 RR024992 from the NIH National Center for Research Resources (NCRR). R.S. conducted this study as partial fulfilment of an international PhD in Molecular Medicine, Vita-Salute San Raffaele University.
Funding Information:
S.A.L., C.D. and J.P.C. received support from an NHLBI T32 Training Grant (HL007088-41). S.M. is supported by a Vallee Scholar Award and an Allen Distinguished Investigator Award. A.D. is supported by the Telethon Foundation (TIGET grants nos. C4 and G3b) and San Raffaele Hospital (Seed Grant). C.M.S. is supported by an American Society of Hematology Scholar Award, an American Society of Hematology Bridge Grant, a Washington University Center of Regenerative Medicine Pilot Grant, the Bill & Melinda Gates Foundation INV-002414, and NIH R01HL145290 and R01HL151777. This publication was made possible, in part, by grant no. UL1 RR024992 from the NIH National Center for Research Resources (NCRR). R.S. conducted this study as partial fulfilment of an international PhD in Molecular Medicine, Vita-Salute San Raffaele University.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/5
Y1 - 2022/5
N2 - The generation of haematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. During embryonic development, HSCs derive from haemogenic endothelium (HE) in a NOTCH- and retinoic acid (RA)-dependent manner. Although a WNT-dependent (WNTd) patterning of nascent hPSC mesoderm specifies clonally multipotent intra-embryonic-like HOXA+ definitive HE, this HE is functionally unresponsive to RA. Here we show that WNTd mesoderm, before HE specification, is actually composed of two distinct KDR+ CD34neg populations. CXCR4negCYP26A1+ mesoderm gives rise to HOXA+ multilineage definitive HE in an RA-independent manner, whereas CXCR4+ALDH1A2+ mesoderm gives rise to HOXA+ multilineage definitive HE in a stage-specific, RA-dependent manner. Furthermore, both RA-independent (RAi) and RA-dependent (RAd) HE harbour transcriptional similarity to distinct populations found in the early human embryo, including HSC-competent HE. This revised model of human haematopoietic development provides essential resolution to the regulation and origins of the multiple waves of haematopoiesis. These insights provide the basis for the generation of specific haematopoietic populations, including the de novo specification of HSCs.
AB - The generation of haematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. During embryonic development, HSCs derive from haemogenic endothelium (HE) in a NOTCH- and retinoic acid (RA)-dependent manner. Although a WNT-dependent (WNTd) patterning of nascent hPSC mesoderm specifies clonally multipotent intra-embryonic-like HOXA+ definitive HE, this HE is functionally unresponsive to RA. Here we show that WNTd mesoderm, before HE specification, is actually composed of two distinct KDR+ CD34neg populations. CXCR4negCYP26A1+ mesoderm gives rise to HOXA+ multilineage definitive HE in an RA-independent manner, whereas CXCR4+ALDH1A2+ mesoderm gives rise to HOXA+ multilineage definitive HE in a stage-specific, RA-dependent manner. Furthermore, both RA-independent (RAi) and RA-dependent (RAd) HE harbour transcriptional similarity to distinct populations found in the early human embryo, including HSC-competent HE. This revised model of human haematopoietic development provides essential resolution to the regulation and origins of the multiple waves of haematopoiesis. These insights provide the basis for the generation of specific haematopoietic populations, including the de novo specification of HSCs.
UR - http://www.scopus.com/inward/record.url?scp=85128931907&partnerID=8YFLogxK
U2 - 10.1038/s41556-022-00898-9
DO - 10.1038/s41556-022-00898-9
M3 - Article
C2 - 35484246
AN - SCOPUS:85128931907
SN - 1465-7392
VL - 24
SP - 616
EP - 624
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 5
ER -