Abstract
BackgroundDespite considerable progress in the development of methods for hematopoietic differentiation, efficient generation of transplantable hematopoietic stem cells (HSCs) and other genuine functional blood cells from human embryonic stem cells (hESCs) is still unsuccessful. Therefore, a better understanding of the molecular mechanism underlying hematopoietic differentiation of hESCs is highly demanded.MethodsIn this study, by using whole-genome gene profiling, we identified Myeloid Ectopic Viral Integration Site 2 homolog (MEIS2) as a potential regulator of hESC early hematopoietic differentiation. We deleted MEIS2 gene in hESCs using the CRISPR/CAS9 technology and induced them to hematopoietic differentiation, megakaryocytic differentiation.ResultsIn this study, we found that MEIS2 deletion impairs early hematopoietic differentiation from hESCs. Furthermore, MEIS2 deletion suppresses hemogenic endothelial specification and endothelial to hematopoietic transition (EHT), leading to the impairment of hematopoietic differentiation. Mechanistically, TAL1 acts as a downstream gene mediating the function of MEIS2 during early hematopoiesis. Interestingly, unlike MEIS1, MEIS2 deletion exerts minimal effects on megakaryocytic differentiation and platelet generation from hESCs.ConclusionsOur findings advance the understanding of human hematopoietic development and may provide new insights for large-scale generation of functional blood cells for clinical applications.
Highlights
Despite considerable progress in the development of methods for hematopoietic differentiation, efficient generation of transplantable hematopoietic stem cells (HSCs) and other genuine functional blood cells from human embryonic stem cells is still unsuccessful
Myeloid Ectopic Viral Integration Site 2 homolog (MEIS2) is a potential regulator of early human hematopoietic differentiation We previously established a chemically defined hematopoietic differentiation system (CDS), which recapitulates embryonic hematopoiesis and allows the cells to go through the stages of mesoderm induction, mesoderm lateralization, hemogenic endothelium progenitor (HEP) specification, and endothelial to hematopoietic transition (EHT) [27, 29] (Fig. 1a)
In attempts to further our understanding of the regulators implicated in early human hematopoietic differentiation, we carried out an in-depth bioinformatics analysis of our previous data of genome-wide RNA-seq
Summary
Despite considerable progress in the development of methods for hematopoietic differentiation, efficient generation of transplantable hematopoietic stem cells (HSCs) and other genuine functional blood cells from human embryonic stem cells (hESCs) is still unsuccessful. Hematopoietic differentiation from hPSCs goes through four main stages: the emergence of mesoderm, the specification of lateral mesoderm, the generation of hemogenic endothelial cells (HEPs), and, the endothelial to hematopoietic transition (EHT), with different molecular markers appearing sequentially during hematopoiesis [7]. TAL1 plays an important role in both HEP generation and hematopoietic transition from endothelium during hematopoiesis of hPSCs [13]. HES1 functions downstream of NOTCH signaling and induces hematopoietic differentiation of hPSCs by refraining the endothelial commitment of HEPs [10]. Identification of novel transcription factors in directing hematopoietic differentiation, especially at the stage of EHT, is essential for a better understanding of hematopoiesis and the de novo generation of clinical-grade HSCs
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