title: A Clinical Indications Prediction Scale Based on TWIST1 for Human Mesenchymal Stem Cells.
abstract: In addition to their stem/progenitor properties, mesenchymal stem cells (MSCs) also exhibit potent effector (angiogenic, antiinflammatory, immuno-modulatory) functions that are largely paracrine in nature. It is widely believed that effector functions underlie most of the therapeutic potential of MSCs and are independent of their stem/progenitor properties. Here we demonstrate that stem/progenitor and effector functions are coordinately regulated at the cellular level by the transcription factor Twist1 and specified within populations according to a hierarchical model. We further show that manipulation of Twist1 levels by genetic approaches or by exposure to widely used culture supplements including fibroblast growth factor 2 (Ffg2) and interferon gamma (IFN-gamma) alters MSC efficacy in cell-based and in vivo assays in a predictable manner. Thus, by mechanistically linking stem/progenitor and effector functions our studies provide a unifying framework in the form of an MSC hierarchy that models the functional complexity of populations. Using this framework, we developed a CLinical Indications Prediction (CLIP) scale that predicts how donor-to-donor heterogeneity and culture conditions impact the therapeutic efficacy of MSC populations for different disease indications.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute - Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Siddaraju V
authors.initials: SV
authors.lastname: Boregowda
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute - Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Veena
authors.initials: V
authors.lastname: Krishnappa
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute - Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Haga
authors.affiliation: Department of Environmental Science and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Ortiz
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute - Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Phinney
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods* / Q000592:standards; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D016222:Fibroblast Growth Factor 2; D007371:Interferon-gamma
keywords: Angiogenesis; Fibroblast Growth Factor; Immuno-suppression; Inflammation; Interferon Gamma; Lung Injury; Mesenchymal Stem Cells; Mesenchymal Stromal Cells; Twist1