MMP13 and TIMP1 are functional markers for two different potential modes of action by mesenchymal stem/stromal cells when treating osteoarthritis. (17th July 2020)

• Record Type: Journal Article
• Authors: Salerno, Anna; Brady, Kyla; Rikkers, Margot; Li, Chao; Caamaño‐Gutierrez, Eva; Falciani, Francesco; Blom, Ashley W.; Whitehouse, Michael R.; Hollander, Anthony P.
• Is Part Of: Stem cells. Volume 38:Number 11(2020)
• Page Start: 1438
• Page End: 1453
• Publication Date: 2020-07-17
• Subjects: chondrogenesis -- mesenchymal stem cells -- MMP13 -- TIMP1 -- trophic repair; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.3255
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: Mesenchymal stem cells (MSCs) have been investigated as a potential injectable therapy for the treatment of knee osteoarthritis, with some evidence of success in preliminary human trials. However, optimization and scale‐up of this therapeutic approach depends on the identification of functional markers that are linked to their mechanism of action. One possible mechanism is through their chondrogenic differentiation and direct role in neo‐cartilage synthesis. Alternatively, they could remain undifferentiated and act through the release of trophic factors that stimulate endogenous repair processes within the joint. Here, we show that extensive in vitro aging of bone marrow‐derived human MSCs leads to loss of chondrogenesis but no reduction in trophic repair, thereby separating out the two modes of action. By integrating transcriptomic and proteomic data using Ingenuity Pathway Analysis, we found that reduced chondrogenesis with passage is linked to downregulation of the FOXM1 signaling pathway while maintenance of trophic repair is linked to CXCL12. In an attempt at developing functional markers of MSC potency, we identified loss of mRNA expression for MMP13 as correlating with loss of chondrogenic potential of MSCs and continued secretion of high levels of TIMP1 protein as correlating with the maintenance of trophic repair capacity. Since an allogeneic injectable osteoar therapy would require extensive cell expansion in vitro, we conclude that early passage MMP13 +, TIMP1‐secreting high MSCs should be used for autologous OA therapies designed to act through engraftment and chondrogenesis, while later passage MMP13 −, TIMP1‐secreting high MSCs could be exploited for allogeneic OA therapies designed to act through trophic repair. Abstract : Aging of human mesenchymal stem/stromal cells in vitro through prolonged culture and passage results in loss of their chondrogenic potential but no reduction in their trophic repair capacity, allowing the identification of gene and protein markers of these different functions.