Hematopoietic Differentiation of Human Pluripotent Stem Cells: HOX and GATA Transcription Factors as Master Regulators

Abstract

Numerous human disorders of the blood system would directly or indirectly benefit from therapeutic approaches that reconstitute the hematopoietic system. Hematopoietic stem cells (HSCs), either from matched donors or ex vivo manipulated autologous tissues, are the most used cellular source of cell therapy for a wide range of disorders. Due to the scarcity of matched donors and the difficulty of ex vivo expansion of HSCs, there is a growing interest in harnessing the potential of pluripotent stem cells (PSCs) as a de novo source of HSCs. PSCs make an ideal source of cells for regenerative medicine in general and for treating blood disorders in particular because they could expand indefinitely in culture and differentiate to any cell type in the body. However, advancement in deriving functional HSCs from PSCs has been slow. This is partly due to an incomplete understanding of the molecular mechanisms underlying normal hematopoiesis. In this review, we discuss the latest efforts to generate human PSC (hPSC)-derived HSCs capable of long-term engraftment. We review the regulation of the key transcription factors (TFs) in hematopoiesis and hematopoietic differentiation, the Homeobox (HOX) and GATA genes, and the interplay between them and microRNAs. We also propose that precise control of these master regulators during the course of hematopoietic differentiation is key to achieving functional hPSC-derived HSCs.

Transcriptome Analyses of β-Thalassemia −28(A>G) Mutation Using Isogenic Cell Models Generated by CRISPR/Cas9 and Asymmetric Single-Stranded Oligodeoxynucleotides (assODNs)

“…In both undifferentiated and differentiated conditions, SPIC and GATA families are predicted as core regulators (Figures 2, 4). The GATA family of transcription factors (GATA1-6) are essential for normal hematopoiesis and a multitude of other developmental processes (Grass et al, 2003;Li et al, 2012;Alsayegh et al, 2019;Castano et al, 2019). GATA-1 regulates terminal differentiation and the function of erythroid, which activates or represses the erythroid-specific gene, such as β-globin locus-binding protein, and it might regulate the switch of fetal to adult hemoglobin in human (Sankaran et al, 2010).…”

Specific Blood Cells Derived from Pluripotent Stem Cells: An Emerging Field with Great Potential in Clinical Cell Therapy

“…In addition to the ongoing challenges of differentiating hPSCs into HSCs that are capable of long-term engraftment, it is necessary to determine the safety of generated blood cells. Accurate control of epigenetic changes in the process of hematopoietic differentiation plays a crucial role in ensuring the safety of generated cells for clinical use [ 111 ]. It has been reported that hematological malignancies can be triggered by the abnormal control of gene expression in HSCs derived from PSCs [ 112 ].…”

Retinoic Acid Promotes Endothelial Cell Cycle Early G1 State to Enable Human Hemogenic Endothelial Cell Specification

“…In contrast, RA upregulated the expression of a number of genes associated with murine hemogenic endothelial cells and HSPCs, including RAR, KIT, NOTCH, CDKN1B, GATA2 and RUNX1. In addition, the expression of a number of SMAD family members was upregulated, as were ligands of the HH and Wnt signaling pathways, and homeobox A1 (HOXA1) genes that are known to play a role in hematopoietic development (Alsayegh et al, 2019). These results are consistent with the gene set enrichment analyses, and suggest that there is potential crosstalk among the RA/HOX/SMAD/HH/ Wnt signaling pathways that instructs the hemogenic specification of endothelial cells and concomitant downregulation of endothelial cell identity.…”