Projektinformation

Beskrivning

The hematopoietic system is continuously replenished from a rare population of hematopoietic stem and progenitor cells (HSPCs) that balance self-renewal and differentiation in order to maintain homeostasis. In contrast to embryonic stem cells (ESCs), and despite extensive functional studies, the intrinsic networks that control hematopoietic stem cell (HSC) fate decisions remain poorly understood, although new studies are starting to make inroads into this maze. Seminal studies by Yamanaka and colleagues in 2006 and 2007 reminded us that transcription factors (TFs) are powerful players in cell fate determination and are sufficient to induce reprogramming towards pluripotency. It has also been demonstrated the direct conversion from one somatic cell fate to another without transiting through pluripotency. Genome-wide approaches have recently started to uncover the underlying mechanisms of induced pluripotency. These studies implicate multiple pathways such as cell cycle, chromatin remodeling, DNA demethylation, and also highlight the mesenchymal-to-epithelial transition. The initial engagement of pluripotency and neural reprogramming factors in the somatic cell genome was recently mapped, providing valuable insights into the initial steps of the reprogramming process. We were the first to demonstrate that somatic cells can be reprogrammed to a somatic stem cell with the degree of multipotency as an HSPC with GATA2, FOS and GFI1B. Multiple laboratories have then reported hematopoietic reprogramming using combinations of TFs starting from multiple somatic cells or pluripotent cells, providing proof of principle that blood stem cells can be generated by direct cell reprogramming. Unfortunately, some of these studies were performed in vivo, which precludes in depth mechanistic studies. In our system from fibroblasts we show that the reprogramming process could induce a dynamic, multi-stage hemogenic process that progresses through an endothelial like intermediate. As such, these TFs induce a process that recapitulates the endothelial-to hematopoietic transition (EHT) during developmental hematopoiesis. The precursor endothelial like cells have a global transcriptional profile highly enriched in vascular and endothelial genes. The hematopoietic cells that emerge afterwards have a gene expression program highly similar to bona fide HSCs in the aorta-gonad-mesonephros, placenta and early fetal liver, where HSCs are generated. Furthermore, the hemogenic reprogramming process appears to recapitulate in vivo developmental definitive hematopoiesis. Despite the obvious broad implications for regenerative medicine and transplantation biology, the ability to initiate a hemogenic process in vitro with a defined combination of TFs offers a tractable system to address the underlying molecular mechanisms of both hematopoietic reprogramming and hematopoiesis in general.
StatusSlutfört
Gällande start-/slutdatum2019/01/012020/12/31

Finansiering

  • Olle Engkvists stiftelse