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SMAD signaling regulates CXCL12 expression in the bone marrow niche, affecting
homing and mobilization of hematopoietic progenitors
#MMPMID25069965
Khurana S
; Melacarne A
; Yadak R
; Schouteden S
; Notelaers T
; Pistoni M
; Maes C
; Verfaillie CM
Stem Cells
2014[Nov]; 32
(11
): 3012-22
PMID25069965
show ga
We recently demonstrated that ex vivo activation of SMAD-independent bone
morphogenetic protein 4 (BMP4) signaling in hematopoietic stem/progenitor cells
(HSPCs) influences their homing into the bone marrow (BM). Here, we assessed
whether alterations in BMP signaling in vivo affects adult hematopoiesis by
affecting the BM niche. We demonstrate that systemic inhibition of SMAD-dependent
BMP signaling by infusion of the BMP antagonist noggin (NGN) significantly
increased CXCL12 levels in BM plasma leading to enhanced homing and engraftment
of transplanted HSPCs. Conversely, the infusion of BMP7 but not BMP4, resulted in
decreased HSPC homing. Using ST2 cells as an in vitro model of BM niche, we found
that incubation with neutralizing anti-BMP4 antibodies, NGN, or dorsomorphin (DM)
as well as knockdown of Smad1/5 and Bmp4, all enhanced CXCL12 production.
Chromatin immunoprecipitation identified the SMAD-binding element in the CXCL12
promoter to which SMAD4 binds. When deleted, increased CXCL12 promoter activity
was observed, and NGN or DM no longer affected Cxcl12 expression. Interestingly,
BMP7 infusion resulted in mobilization of only short-term HSCs, likely because
BMP7 affected CXCL12 expression only in osteoblasts but not in other niche
components. Hence, we describe SMAD-dependent BMP signaling as a novel regulator
of CXCL12 production in the BM niche, influencing HSPC homing, engraftment, and
mobilization.
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