Hedgehog signaling is dispensable for adult hematopoietic stem cell function.
The Hedgehog (Hh) signaling pathway is a developmentally conserved regulator of stem cell function. Several reports suggested that Hh signaling is an important regulator of hematopoietic stem cell (HSC) maintenance and differentiation. Here we test this hypothesis in vivo using both gain- and loss-of-function Hh genetic models. Surprisingly, our studies demonstrate that conditional Smoothened (Smo) deletion or overactivation has no significant effects on adult HSC self-renewal and function. Moreover, they indicate a lack of synergism between the Notch and Hh pathways in HSC function, as compound RBPJ and Smo deficiency does not affect hematopoiesis. In agreement with this notion, detailed genome-wide transcriptome analysis reveals that silencing of Hh signaling does not significantly alter the HSC-specific gene expression "signature." Our studies demonstrate that the Hh signaling pathway is dispensable for adult HSC function and suggest that Hh inhibition on leukemia-initiating cell maintenance can be targeted in future clinical trials.
Gao
Jie
J
Department of Pathology and NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
Graves
Stephanie
S
Koch
Ute
U
Liu
Suqing
S
Jankovic
Vladimir
V
Buonamici
Silvia
S
El Andaloussi
Abdeljabar
A
Nimer
Stephen D
SD
Kee
Barbara L
BL
Taichman
Russell
R
Radtke
Freddy
F
Aifantis
Iannis
I
D053687:Adult Stem Cells; D000818:Animals; D002454:Cell Differentiation; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006706:Homeostasis; D007938:Leukemia; D051379:Mice; D008815:Mice, Inbred Strains; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor
D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; D051880:Receptors, Notch; C491023:SMO protein, human; D000072086:Smoothened Receptor