Transcription Factor Cooperation Drives Human Hematopoietic Stem and Progenitor Cell Specification

Review of “Cooperative Transcription Factor Induction Mediates Hemogenic Reprogramming” from Cell Reports by Stuart P. Atkinson 

Studies focusing on early hematopoietic progenitor and stem cell specification from the research group of Carlos-Filipe Pereira (Lund University, Lund, Sweden) demonstrated that the forced expression of the GATA2, FOS, and GFI1B transcription factors transited mouse fibroblasts through an endothelial-like intermediate to a hemogenic precursor cell fate [1]. Encouragingly, these findings aided the in vivo identification of a mouse cell population expressing endothelial and early hematopoietic markers in the mouse placenta [2], suggesting that the reprogramming of mouse fibroblasts to hemogenic precursor cells recapitulates developmental hematopoiesis.

The team now returns with a Cell Reports study in which they shift their focus from the specification of mouse to human hematopoietic stem cells and describe the generation of hemogenic precursors from human fibroblasts via an endothelial intermediate and highlight the general importance of transcription factor cooperation during human hematopoietic stem cell specification [3].

The authors discovered that human fibroblasts, in a similar manner to mouse fibroblasts, underwent reprogramming through an intermediate endothelial stage (as marked by the expression of the PPARG, VWF, and FOXC2 angiogenesis-associated genes) to a hemogenic precursor cell fate following the forced expression of the GATA2, GFI1B, and FOS transcription factors. Said hemogenic precursors displayed endothelial-to-hematopoietic transcriptional programs, gave rise to hematopoietic lineage cells, exhibited a hematopoietic stem and progenitor cell surface phenotype, and engrafted in immunodeficient mice to produce multi-lineage hematopoietic progeny for three months. 

During mechanistic studies, the authors confirmed that collaborative interactions between the three transcription factors initiated the silencing of fibroblastic gene expression and then activated endothelial and hematopoietic gene expression. While GATA2 displayed dominant and independent targeting activity during the early phases of fibroblast reprogramming, GATA2 also functioned by recruiting GFI1B to bind open chromatin regions to control gene expression programs cooperatively.

Overall, the authors establish GATA2, GFI1B, and FOS as a conserved minimal transcription factor network for hemogenic induction in both mouse and human and further demonstrate how direct cellular reprogramming can provide insight into the molecular mechanisms of human hematopoietic stem cell specification. Excitingly, the authors anticipate that their findings will also act as a platform for the development of patient-specific hematopoietic stem and progenitor cells from easily accessible patient-derived human dermal fibroblasts.

For more on direct reprogramming and the mechanisms controlling hematopoietic specifications in humans, stay tuned to the Stem Cells Portal!

References

1. Pereira C-F, Chang B, Qiu J, et al., Induction of a Hemogenic Program in Mouse Fibroblasts. Cell Stem Cell 2013;13:205-218.
2. Pereira C-F, Chang B, Gomes A, et al., Hematopoietic Reprogramming In Vitro Informs In Vivo Identification of Hemogenic Precursors to Definitive Hematopoietic Stem Cells. Developmental Cell 2016;36:525-539.
3. Gomes AM, Kurochkin I, Chang B, et al., Cooperative Transcription Factor Induction Mediates Hemogenic Reprogramming. Cell Reports 2018;25:2821-2835.e7.