title: ECM microenvironment unlocks brown adipogenic potential of adult human bone marrow-derived MSCs.
abstract: Key to realizing the diagnostic and therapeutic potential of human brown/brite adipocytes is the identification of a renewable, easily accessible and safe tissue source of progenitor cells, and an efficacious in vitro differentiation protocol. We show that macromolecular crowding (MMC) facilitates brown adipocyte differentiation in adult human bone marrow mesenchymal stem cells (bmMSCs), as evidenced by substantially upregulating uncoupling protein 1 (UCP1) and uncoupled respiration. Moreover, MMC also induced 'browning' in bmMSC-derived white adipocytes. Mechanistically, MMC creates a 3D extracellular matrix architecture enshrouding maturing adipocytes in a collagen IV cocoon that is engaged by paxillin-positive focal adhesions also at the apical side of cells, without contact to the stiff support structure. This leads to an enhanced matrix-cell signaling, reflected by increased phosphorylation of ATF2, a key transcription factor in UCP1 regulation. Thus, tuning the dimensionality of the microenvironment in vitro can unlock a strong brown potential dormant in bone marrow.
authors.affiliation: Department of Biomedical Engineering, National University of Singapore, 117575, Singapore.|NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, 117456, Singapore.|NUS Tissue Engineering Program, Life Science Institute, National University of Singapore, 117510, Singapore.
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Department of Biomedical Engineering, National University of Singapore, 117575, Singapore.|NUS Tissue Engineering Program, Life Science Institute, National University of Singapore, 117510, Singapore.
authors.forename: Anna G
authors.initials: AG
authors.lastname: Goralczyk
authors.affiliation: Department of Biomedical Engineering, National University of Singapore, 117575, Singapore.|NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, 117456, Singapore.|NUS Tissue Engineering Program, Life Science Institute, National University of Singapore, 117510, Singapore.
authors.forename: Rókus
authors.initials: R
authors.lastname: Kriszt
authors.affiliation: Department of Biomedical Engineering, National University of Singapore, 117575, Singapore.|NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, 117456, Singapore.|NUS Tissue Engineering Program, Life Science Institute, National University of Singapore, 117510, Singapore.
authors.forename: Xiu Min
authors.initials: XM
authors.lastname: Ang
authors.affiliation: Institute of Medical Biology, A*STAR, 138648, Singapore.
authors.forename: Cedric
authors.initials: C
authors.lastname: Badowski
authors.affiliation: Program in Cardiovascular and Metabolic Diseases, Duke-NUS Medical Graduate School, 169857, Singapore.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Translational Metabolic Health Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne VIC 3004, Australia.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Summers
authors.affiliation: Department of Medicine, National University Health System, 119228, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 117599, Singapore.
authors.forename: Sue-Anne
authors.initials: SA
authors.lastname: Toh
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 117599, Singapore.
authors.forename: M Shabeer
authors.initials: MS
authors.lastname: Yassin
authors.affiliation: Department of Surgery, National University Hospital, 119074, Singapore.
authors.forename: Asim
authors.initials: A
authors.lastname: Shabbir
authors.affiliation: Liggins Institute, University of Auckland, Auckland 1142 New Zealand.
authors.forename: Allan
authors.initials: A
authors.lastname: Sheppard
authors.affiliation: Department of Biomedical Engineering, National University of Singapore, 117575, Singapore.|NUS Tissue Engineering Program, Life Science Institute, National University of Singapore, 117510, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117599, Singapore.
authors.forename: Michael
authors.initials: M
authors.lastname: Raghunath
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D052437:Adipocytes, Brown / Q000166:cytology / Q000378:metabolism; D052438:Adipocytes, White / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis; D002454:Cell Differentiation; D060833:Cellular Microenvironment; D005109:Extracellular Matrix / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008954:Models, Biological; D010641:Phenotype; D050507:Subcutaneous Fat, Abdominal / Q000166:cytology / Q000378:metabolism; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D051698:Activating Transcription Factor 2; D000071256:Uncoupling Protein 1