title: Abi3bp is a multifunctional autocrine/paracrine factor that regulates mesenchymal stem cell biology.
abstract: Mesenchymal stem cells (MSCs) transplanted into injured myocardium promote repair through paracrine mechanisms. We have previously shown that MSCs over-expressing AKT1 (Akt-MSCs) exhibit enhanced properties for cardiac repair. In this study, we investigated the relevance of Abi3bp toward MSC biology. Abi3bp formed extracellular deposits with expression controlled by Akt1 and ubiquitin-mediated degradation. Abi3bp knockdown/knockout stabilized focal adhesions and promoted stress-fiber formation. Furthermore, MSCs from Abi3bp knockout mice displayed severe deficiencies in osteogenic and adipogenic differentiation. Knockout or stable knockdown of Abi3bp increased MSC and Akt-MSC proliferation, promoting S-phase entry via cyclin-d1, ERK1/2, and Src. Upon Abi3bp binding to integrin-β1 Src associated with paxillin which inhibited proliferation. In vivo, Abi3bp knockout increased MSC number and proliferation in bone marrow, lung, and liver. In summary, we have identified a novel extracellular matrix protein necessary for the switch from proliferation to differentiation in MSCs.
authors.affiliation: Mandel Center for Hypertension Research and Division of Cardiovascular Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Conrad P
authors.initials: CP
authors.lastname: Hodgkinson
authors.forename: Vinogran
authors.initials: V
authors.lastname: Naidoo
authors.forename: Karl G
authors.initials: KG
authors.lastname: Patti
authors.forename: Jose A
authors.initials: JA
authors.lastname: Gomez
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schmeckpeper
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Bryce
authors.initials: B
authors.lastname: Davis
authors.forename: Richard E
authors.initials: RE
authors.lastname: Pratt
authors.forename: Maria
authors.initials: M
authors.lastname: Mirotsou
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Dzau
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019899:Paracrine Communication; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C527603:TARSH protein, mouse; D025801:Ubiquitin; D051057:Proto-Oncogene Proteins c-akt
keywords: Cell signaling; Extracellular matrix; Integrin; Mesenchymal stem cells