TGFβ restores hematopoietic homeostasis after myelosuppressive chemotherapy. Academic Article uri icon

Overview

MeSH

  • Animals
  • Cyclin-Dependent Kinase Inhibitor p57
  • Hematopoietic Stem Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction

MeSH Major

  • Antineoplastic Agents
  • Bone Marrow
  • Hematopoiesis
  • Homeostasis
  • Transforming Growth Factor beta

abstract

  • Myelosuppression is a life-threatening complication of antineoplastic therapy, but treatment is restricted to a few cytokines with unilineage hematopoietic activity. Although hematopoietic stem cells (HSCs) are predominantly quiescent during homeostasis, they are rapidly recruited into cell cycle by stresses, including myelosuppressive chemotherapy. Factors that induce HSCs to proliferate during stress have been characterized, but it is not known how HSC quiescence is then reestablished. In this study, we show that TGFβ signaling is transiently activated in hematopoietic stem and progenitor cells (HSPCs) during hematopoietic regeneration. Blockade of TGFβ signaling after chemotherapy accelerates hematopoietic reconstitution and delays the return of cycling HSCs to quiescence. In contrast, TGFβ blockade during homeostasis fails to induce cycling of HSPCs. We identified the cyclin-dependent kinase inhibitor Cdkn1c (p57) as a key downstream mediator of TGFβ during regeneration because the recovery of chimeric mice, incapable of expressing p57 in HSPCs, phenocopies blockade of TGFβ signaling after chemotherapy. This study demonstrates that context-dependent activation of TGFβ signaling is central to an unrecognized counterregulatory mechanism that promotes homeostasis once hematopoiesis has sufficiently recovered from myelosuppressive chemotherapy. These results open the door to new, potentially superior, approaches to promote multilineage hematopoietic recovery by blocking the TGFβ signaling that dampens regeneration.

publication date

  • March 11, 2013

has subject area

  • Animals
  • Antineoplastic Agents
  • Bone Marrow
  • Cyclin-Dependent Kinase Inhibitor p57
  • Hematopoiesis
  • Hematopoietic Stem Cells
  • Homeostasis
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction
  • Transforming Growth Factor beta

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3600905

Digital Object Identifier (DOI)

  • 10.1084/jem.20121610

PubMed ID

  • 23440043

Additional Document Info

start page

  • 623

end page

  • 639

volume

  • 210

number

  • 3