title: MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells.
abstract: Expansion on stiff culture substrates activates pro-fibrotic cell programs that are retained by mechanical memory. Here, we show that priming on physiologically soft silicone substrates suppresses fibrogenesis and desensitizes mesenchymal stem cells (MSCs) against subsequent mechanical activation in vitro and in vivo, and identify the microRNA miR-21 as a long-term memory keeper of the fibrogenic program in MSCs. During stiff priming, miR-21 levels were gradually increased by continued regulation through the acutely mechanosensitive myocardin-related transcription factor-A (MRTF-A/MLK-1) and remained high over 2 weeks after removal of the mechanical stimulus. Knocking down miR-21 once by the end of the stiff-priming period was sufficient to erase the mechanical memory and sensitize MSCs to subsequent exposure to soft substrates. Soft priming and erasing mechanical memory following cell culture expansion protects MSCs from fibrogenesis in the host wound environment and increases the chances for success of MSC therapy in tissue-repair applications.
authors: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors: Chen Xi
authors: CX
authors: Li
authors: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors: Nilesh P
authors: 0000-0003-2758-8599
authors: NP
authors: Talele
authors: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors: Stellar
authors: S
authors: Boo
authors: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors: Anne
authors: A
authors: Koehler
authors: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors: Ericka
authors: E
authors: Knee-Walden
authors: Draper, Cambridge, Massachusetts 02139, USA.
authors: Jenna L
authors: JL
authors: Balestrini
authors: Keenan Research Centre in the Li Ka Shing Knowledge Institute in the St. Michael's Hospital, and Department of Surgery, University of Toronto, Toronto, Ontario M5B 1W8, Canada.
authors: Pam
authors: P
authors: Speight
authors: Keenan Research Centre in the Li Ka Shing Knowledge Institute in the St. Michael's Hospital, and Department of Surgery, University of Toronto, Toronto, Ontario M5B 1W8, Canada.
authors: Andras
authors: A
authors: Kapus
authors: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors: Boris
authors: 0000-0002-0526-393X
authors: B
authors: Hinz
mesh_terms: D000818:Animals; D005355:Fibrosis; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013314:Stress, Mechanical; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D014157:Transcription Factors; C546082:mirn21 microRNA, rat; C557977:myocardin-related transcription factor-A, rat