TY - JOUR
T1 - Dynamic WNT signaling controls differentiation of hematopoietic progenitor cells from human pluripotent stem cells
AU - Li, Mo
AU - Suzuki, Keiichiro
AU - Wang, Mengge
AU - Benner, Christopher
AU - Ku, Manching
AU - Ma, Li
AU - Kobari, Ladan
AU - Kim, Na Young
AU - Montserrat, Nuria
AU - Chang, Chan Jung
AU - Liu, Guanghui
AU - Qu, Jing
AU - Xu, Jinna
AU - Zhang, Yingzi
AU - Aizawa, Emi
AU - Wu, Jun
AU - Douay, Luc
AU - Esteban, Concepcion Rodriguez
AU - Belmonte, Juan Carlos Izpisua
N1 - Publisher Copyright:
© Science China Press 2025.
PY - 2025
Y1 - 2025
N2 - Human pluripotent stem cells (hPSCs) can in theory give rise to any hematopoietic lineages, thereby offering opportunities for disease modeling, drug screening and cell therapies. However, gaps in our knowledge of the signaling requirements for the specification of human hematopoietic stem/progenitor cells (HSPCs), which lie at the apex of all hematopoietic lineages, greatly limit the potential of hPSC in hematological research and application. Transcriptomic analysis reveals aberrant regulation of WNT signaling during maturation of hPSC-derived hematopoietic progenitor cells (hPSC-HPCs), which results in higher mitochondria activity, misregulation of HOX genes, loss of self-renewal and precocious differentiation. These defects are partly due to the activation of the WNT target gene CDX2. Late-stage WNT inhibition improves the yield, self-renewal, multilineage differentiation, and transcriptional and metabolic profiles of hPSC-HPCs. Genome-wide mapping of transcription factor (TF) accessible chromatin reveals a significant overrepresentation of myeloid TF binding motifs in hPSC-HPCs, which could underlie their myeloid-biased lineage potential. Together our findings uncover a previously unappreciated dynamic requirement of the WNT signaling pathway during the specification of human HSPCs. Modulating the WNT pathway with small molecules normalizes the molecular differences between hPSC-HPCs and endogenous hematopoietic stem cells (HSCs), thereby representing a promising approach to improve the differentiation and function of hPSC-HPCs.
AB - Human pluripotent stem cells (hPSCs) can in theory give rise to any hematopoietic lineages, thereby offering opportunities for disease modeling, drug screening and cell therapies. However, gaps in our knowledge of the signaling requirements for the specification of human hematopoietic stem/progenitor cells (HSPCs), which lie at the apex of all hematopoietic lineages, greatly limit the potential of hPSC in hematological research and application. Transcriptomic analysis reveals aberrant regulation of WNT signaling during maturation of hPSC-derived hematopoietic progenitor cells (hPSC-HPCs), which results in higher mitochondria activity, misregulation of HOX genes, loss of self-renewal and precocious differentiation. These defects are partly due to the activation of the WNT target gene CDX2. Late-stage WNT inhibition improves the yield, self-renewal, multilineage differentiation, and transcriptional and metabolic profiles of hPSC-HPCs. Genome-wide mapping of transcription factor (TF) accessible chromatin reveals a significant overrepresentation of myeloid TF binding motifs in hPSC-HPCs, which could underlie their myeloid-biased lineage potential. Together our findings uncover a previously unappreciated dynamic requirement of the WNT signaling pathway during the specification of human HSPCs. Modulating the WNT pathway with small molecules normalizes the molecular differences between hPSC-HPCs and endogenous hematopoietic stem cells (HSCs), thereby representing a promising approach to improve the differentiation and function of hPSC-HPCs.
KW - EHT
KW - hematopoietic differentiation
KW - HPCs
KW - hPSCs
KW - WNT signaling
UR - http://www.scopus.com/inward/record.url?scp=105000028417&partnerID=8YFLogxK
U2 - 10.1007/s11427-024-2816-0
DO - 10.1007/s11427-024-2816-0
M3 - Article
C2 - 40080269
AN - SCOPUS:105000028417
SN - 1674-7305
JO - Science China Life Sciences
JF - Science China Life Sciences
ER -
