TY - JOUR
T1 - Human definitive hematopoietic specification from pluripotent stem cells is regulated by mesodermal expression of CDX4
AU - Philip Creamer, J.
AU - Dege, Carissa
AU - Ren, Qihao
AU - Ho, Jolie T.K.
AU - Valentine, Mark C.
AU - Druley, Todd E.
AU - Sturgeon, Christopher M.
N1 - Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - The generation of hematopoietic stem cells from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. Achieving this goal is complicated by our incomplete understanding of the mechanism regulating definitive hematopoietic specification. We used our stage-specific hPSC differentiation method to obtain and identify, via CD235a expression, mesoderm harboring exclusively primitive or definitive hematopoietic potential to understand the genetic regulation of definitive hematopoietic specification. Whole-Transcriptome gene expression analyses on WNT-dependent KDR1 CD235a2 definitive hematopoietic mesoderm and WNT-independent KDR1CD235a1 primitive hematopoietic mesoderm revealed strong CDX gene expression within definitive hematopoieticmesoderm. Temporal expression analyses revealed that CDX4 was expressed exclusively within definitive hematopoietic KDR1CD235a2 mesoderm in a WNT-and fibroblast growth factor-dependent manner. We found that exogenous CDX4 expression exclusively during mesoderm specification resulted in a >90% repression in primitive hematopoietic potential, but conferred fivefold greater definitive hematopoietic potential, similar to that observed following WNT stimulation. In contrast, CDX4 knockout hPSCs had intact primitive hematopoietic potential, but exhibited a fivefold decrease in multilineage definitive hematopoietic potential. Taken together, these findings indicate that CDX4 is a critical transcription factor in the regulationofhumandefinitivehematopoieticspecification,andprovides amechanisticbasis forWNT-mediateddefinitivehematopoietic specification from hPSCs.
AB - The generation of hematopoietic stem cells from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. Achieving this goal is complicated by our incomplete understanding of the mechanism regulating definitive hematopoietic specification. We used our stage-specific hPSC differentiation method to obtain and identify, via CD235a expression, mesoderm harboring exclusively primitive or definitive hematopoietic potential to understand the genetic regulation of definitive hematopoietic specification. Whole-Transcriptome gene expression analyses on WNT-dependent KDR1 CD235a2 definitive hematopoietic mesoderm and WNT-independent KDR1CD235a1 primitive hematopoietic mesoderm revealed strong CDX gene expression within definitive hematopoieticmesoderm. Temporal expression analyses revealed that CDX4 was expressed exclusively within definitive hematopoietic KDR1CD235a2 mesoderm in a WNT-and fibroblast growth factor-dependent manner. We found that exogenous CDX4 expression exclusively during mesoderm specification resulted in a >90% repression in primitive hematopoietic potential, but conferred fivefold greater definitive hematopoietic potential, similar to that observed following WNT stimulation. In contrast, CDX4 knockout hPSCs had intact primitive hematopoietic potential, but exhibited a fivefold decrease in multilineage definitive hematopoietic potential. Taken together, these findings indicate that CDX4 is a critical transcription factor in the regulationofhumandefinitivehematopoieticspecification,andprovides amechanisticbasis forWNT-mediateddefinitivehematopoietic specification from hPSCs.
UR - http://www.scopus.com/inward/record.url?scp=85020301298&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-11-749382
DO - 10.1182/blood-2016-11-749382
M3 - Article
C2 - 28408465
AN - SCOPUS:85020301298
SN - 0006-4971
VL - 129
SP - 2988
EP - 2992
JO - Blood
JF - Blood
IS - 22
ER -