Hematopoietic stem cell responsiveness to exogenous signals is limited by caspase-3.
Limited responsiveness to inflammatory cytokines is a feature of adult hematopoietic stem cells and contributes to the relative quiescence and durability of the stem cell population in vivo. Here we report that the executioner Caspase, Caspase-3, unexpectedly participates in that process. Mice deficient in Caspase-3 had increased numbers of immunophenotypic long-term repopulating stem cells in association with multiple functional changes, most prominently cell cycling. Though these changes were cell autonomous, they reflected altered activation by exogenous signals. Caspase-3(-/-) cells exhibited cell type-specific changes in phosphorylated members of the Ras-Raf-MEK-ERK pathway in response to specific cytokines, while notably, members of other pathways, such as pSTAT3, pSTAT5, pAKT, pp38 MAPK, pSmad2, and pSmad3, were unaffected. Caspase-3 contributes to stem cell quiescence, dampening specific signaling events and thereby cell responsiveness to microenvironmental stimuli.
Janzen
Viktor
V
Center for Regenerative Medicine, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Fleming
Heather E
HE
Riedt
Tamara
T
Karlsson
Göran
G
Riese
Matthew J
MJ
Lo Celso
Cristina
C
Reynolds
Griffin
G
Milne
Craig D
CD
Paige
Christopher J
CJ
Karlsson
Stefan
S
Woo
Minna
M
Scadden
David T
DT
D000818:Animals; D053148:Caspase 3 / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D016207:Cytokines; D048490:raf Kinases; D020930:MAP Kinase Kinase Kinases; C096335:B59 protein, human; D017027:Protein Tyrosine Phosphatases; D053148:Caspase 3; D018631:ras Proteins