title: Brief report: the differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation.
abstract: Adipocytes (AdCs) and osteoblasts (OBs) are derived from mesenchymal stem cells (MSCs) and differentiation toward either lineage is both mutually exclusive and transcriptionally controlled. Recent studies implicate the mammalian target of rapamycin (mTOR) pathway as important in determining MSC fate, with inhibition of mTOR promoting OB differentiation and suppressing AdC differentiation. mTOR functions within two distinct multiprotein complexes, mTORC1 and mTORC2, each of which contains the unique adaptor protein, raptor or rictor, respectively. While compounds used to study mTOR signaling, such as rapamycin and related analogs, primarily inhibit mTORC1, prolonged exposure can also disrupt mTORC2 function, confounding interpretation of inhibitor studies. As a result, the relative contribution of mTORC1 and mTORC2 to MSC fate determination remains unclear. In this study, we generated primary mouse MSCs deficient in either Rptor (RapKO) or Rictor (RicKO) using the Cre/loxP system. Cre-mediated deletion of Rptor or Rictor resulted in impaired mTORC1 and mTORC2 signaling, respectively. Under lineage-inductive culture conditions, RapKO MSCs displayed a reduced capacity to form lipid-laden AdCs and an increased capacity to form a mineralized matrix. In contrast, RicKO MSCs displayed reduced osteogenic differentiation capacity and enhanced adipogenic differentiation potential. Taken together, our findings reveal distinct roles for mTORC1 and mTORC2 in MSC lineage commitment.
authors.affiliation: Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia; Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia; Centre for Stem Cell Research, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Sally K
authors.initials: SK
authors.lastname: Martin
authors.forename: Stephen
authors.initials: S
authors.lastname: Fitter
authors.forename: Ankit K
authors.initials: AK
authors.lastname: Dutta
authors.forename: Mary P
authors.initials: MP
authors.lastname: Matthews
authors.forename: Carl R
authors.initials: CR
authors.lastname: Walkley
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.forename: Markus A
authors.initials: MA
authors.lastname: Ruegg
authors.forename: Stan
authors.initials: S
authors.lastname: Gronthos
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: Mesenchymal stem cell; Raptor; Rictor; mTOR