Human definitive hematopoietic specification from pluripotent stem cells is regulated by mesodermal expression of CDX4
| Autor: | Todd E. Druley, Jolie T. K. Ho, Carissa Dege, Christopher M. Sturgeon, Mark C. Valentine, Qihao Ren, J. Philip Creamer |
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| Rok vydání: | 2017 |
| Předmět: |
Pluripotent Stem Cells
0301 basic medicine Mesoderm animal structures Immunology Biology Biochemistry Regenerative medicine Cell Line Gene Knockout Techniques 03 medical and health sciences 0302 clinical medicine medicine Humans Cell Lineage Glycophorins Induced pluripotent stem cell Wnt Signaling Pathway Homeodomain Proteins Regulation of gene expression Wnt signaling pathway Gene Expression Regulation Developmental Cell Biology Hematology Hematopoietic Stem Cells Vascular Endothelial Growth Factor Receptor-2 Hematopoiesis And Stem Cells Hematopoiesis Cell biology Transplantation Haematopoiesis 030104 developmental biology medicine.anatomical_structure embryonic structures Stem cell 030217 neurology & neurosurgery |
| Zdroj: | Blood. 129:2988-2992 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2016-11-749382 |
| Popis: | 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 KDR+CD235a- definitive hematopoietic mesoderm and WNT-independent KDR+CD235a+ primitive hematopoietic mesoderm revealed strong CDX gene expression within definitive hematopoietic mesoderm. Temporal expression analyses revealed that CDX4 was expressed exclusively within definitive hematopoietic KDR+CD235a- 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 regulation of human definitive hematopoietic specification, and provides a mechanistic basis for WNT-mediated definitive hematopoietic specification from hPSCs. |
| Databáze: | OpenAIRE |
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