Hedgehog modulates cell cycle regulators in stem cells to control hematopoietic regeneration.
The signals that control the regenerative ability of hematopoietic stem cells (HSCs) in response to damage are unknown. Here, we demonstrate that downstream activation of the Hedgehog (Hh) signaling pathway induces cycling and expansion of primitive bone marrow hematopoietic cells under homeostatic conditions and during acute regeneration. However, this effect is at the expense of HSC function, because continued Hh activation during regeneration represses expression of specific cell cycle regulators, leading to HSC exhaustion. In vivo treatment with an inhibitor of the Hh pathway rescues these transcriptional and functional defects in HSCs. Our study establishes Hh signaling as a regulator of the HSC cell cycle machinery that balances hematopoietic homeostasis and regeneration in vivo.
Trowbridge
Jennifer J
JJ
Department of Microbiology and Immunology, University of Western Ontario, 1151 Richmond Street, Suite 2, London, ON, Canada N6A 5B8.
Scott
Matthew P
MP
Bhatia
Mickie
M
D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D000072079:Patched Receptors; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014704:Veratrum Alkaloids / Q000378:metabolism
D000950:Antigens, Ly; D018797:Cell Cycle Proteins; D053823:Hedgehog Proteins; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D019009:Proto-Oncogene Proteins c-kit; C000541:cyclopamine