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.
Center for Regenerative Medicine, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Viktor
V
Janzen
Heather E
HE
Fleming
Tamara
T
Riedt
Göran
G
Karlsson
Matthew J
MJ
Riese
Cristina
C
Lo Celso
Griffin
G
Reynolds
Craig D
CD
Milne
Christopher J
CJ
Paige
Stefan
S
Karlsson
Minna
M
Woo
David T
DT
Scadden
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