Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells.
Although recent data suggests that osteoblasts play a key role within the hematopoietic stem cell (HSC) niche, the mechanisms underpinning this remain to be fully defined. The studies described herein examine the role in hematopoiesis of Osteopontin (Opn), a multidomain, phosphorylated glycoprotein, synthesized by osteoblasts, with well-described roles in cell adhesion, inflammatory responses, angiogenesis, and tumor metastasis. We demonstrate a previously unrecognized critical role for Opn in regulation of the physical location and proliferation of HSCs. Within marrow, Opn expression is restricted to the endosteal bone surface and contributes to HSC transmarrow migration toward the endosteal region, as demonstrated by the markedly aberrant distribution of HSCs in Opn-/- mice after transplantation. Primitive hematopoietic cells demonstrate specific adhesion to Opn in vitro via beta1 integrin. Furthermore, exogenous Opn potently suppresses the proliferation of primitive HPCs in vitro, the physiologic relevance of which is demonstrated by the markedly enhanced cycling of HSC in Opn-/- mice. These data therefore provide strong evidence that Opn is an important component of the HSC niche which participates in HSC location and as a physiologic-negative regulator of HSC proliferation.
Nilsson
Susan K
SK
Stem Cell Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Melbourne, Victoria, Australia, 3000. susie.nilsson@petermac.org
Johnston
Hayley M
HM
Whitty
Genevieve A
GA
Williams
Brenda
B
Webb
Ryan J
RJ
Denhardt
David T
DT
Bertoncello
Ivan
I
Bendall
Linda J
LJ
Simmons
Paul J
PJ
Haylock
David N
DN
D000818:Animals; D001853:Bone Marrow / Q000737:chemistry; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053495:Osteopontin; D012795:Sialoglycoproteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D014018:Tissue Distribution
D019012:Integrin beta1; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin