New research suggests proinflammatory signaling is crucial to the creation of hematopoietic stem cells (HSCs) during embryonic development, a finding that could help scientists reproduce HSCs for therapeutic use.
Researchers discovered that TNFR2, via TNFα, activates the Notch and NF-kB signaling pathways to establish HSC fate, which suggests inflammatory signaling is required for HSC generation.
The group also found that primitive neutrophils are the major source of TNFa. So it seems these cells are crucial to HSC development as well.
The researchers described these findings in Cell.
“The development of some mature cell lineages from iPSCs [induced pluripotent stem cells], such as cardiac and neural, has been reasonably straightforward, but not with HSCs,” said principal investigator David Traver, PhD, of the University of California, San Diego School of Medicine.
“This is likely due, at least in part, to not fully understanding all of the factors used by the embryo to generate HSCs. We believe the discovery that proinflammatory cues are important in vivo will help us recapitulate instruction of HSC fate in vitro from iPSCs.”
For this study, Dr Traver and his colleagues decided to examine the role of TNFα in HSC development, extending previous research by Victoriano Mulero, PhD, of the University of Murcia in Spain.
Dr Mulero reported that TNFα is important in the function of the embryonic vascular system. And, in animal models where TNF function was absent, blood defects resulted.
Raquel Espin-Palazon, PhD, a researcher in Dr Traver’s lab and a former colleague of Dr Mulero’s, determined that TNFα is required for the emergence of HSCs during embryogenesis in zebrafish.
Dr Traver said the finding was completely unexpected because HSCs emerge relatively early in embryonic formation, when the developing organism is considered to be largely sterile and devoid of infection.
“Thus, there was no expectation that proinflammatory signaling would be active at this time or in the blood-forming regions,” Dr Traver said. “Equally surprising, we found that a population of embryonic myeloid cells, which are transient cells produced before HSCs arise, are the producers of the TNFα needed to establish HSC fate.”
“So it turns out that a small subset of myeloid cells that persist for only a few days in development are necessary to help generate the lineal precursors of the entire adult blood-forming system.”
