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Review
. 2019 Jun;37(6):1236-1245.
doi: 10.1002/jor.24266. Epub 2019 Mar 21.

Prospective application of stem cells to prevent post-operative skeletal fibrosis

Xiaolei Li  1   2 , Song Chen  3 , Lianqi Yan  1 , Jingcheng Wang  1 , Ming Pei  2   4   5
Affiliations
Review

Prospective application of stem cells to prevent post-operative skeletal fibrosis

Xiaolei Li et al. J Orthop Res. 2019 Jun.

Abstract

Post-operative skeletal fibrosis is considered one of the major complications causing dysfunction of the skeletal system and compromising the outcomes of clinical treatment. Limited success has been achieved using current therapies; more effective therapies to reduce post-operative skeletal fibrosis are needed. Stem cells possess the ability to repair and regenerate damaged tissue. Numerous studies show that stem cells serve as a promising therapeutic approach for fibrotic diseases in tissues other than the skeletal system by inhibiting the inflammatory response and secreting favorable cytokines through activating specific signaling pathways, acting as so-called medicinal signaling cells. In this review, current therapies are summarized for post-operative skeletal fibrosis. Given that stem cells are used as a promising therapeutic approach for fibrotic diseases, little effort has been undertaken to use stem cells to prevent post-operative skeletal fibrosis. This review aims at providing useful information for the potential application of stem cells in preventing post-operative skeletal fibrosis in the near future. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1236-1245, 2019.

Keywords: epidural fibrosis; intraarticular fibrosis; peritendinous fibrosis; post-operative skeletal fibrosis; stem cell.

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Figures

Figure 1.
Figure 1.
Potential interference of stem cells on fibrosis formation. Cellular and molecular pathways include tissue injury and/or repair triggering secretion of cytokines (VEGF, TGF-β, IL-1, TNF-α, IFN-γ, PDGF) by mast cells, macrophages, lymphocytes, monocytes, basophils and eosinophils that lead to activation of fibroblasts via trans-differentiation of epithelial cells and fibrocytes and further into myofibroblasts. Cytokines and exosomes secreted by stem cells could inhibit fibroblast activation and other cell types to trans-differentiate into myofibroblasts, resulting in upregulation of MMPs and downregulation of TIMPs and α-SMA which leads to inhibition of fibrosis formation.
Figure 2.
Figure 2.
Main cytokine pathways regulating tissue fibrosis. Cytokines (TGF-β, IL-1, TNF-α, IFN-γ, PDGF) secreted by inflammatory cells mediate the activation of several intracellular signaling pathways. As a major fibrogenic cytokine, TGF-β activates the canonical and noncanonical pathway resulting in induction of fibrogenic genes, such as collagen I/III/IV, TIMPs and α-SMA. Other cytokines, such as PDGF, IFN-γ, IL-1 and TNF-α, are also involved in regulating fibrosis formation primarily through their binding to specific receptors. Cytokines secreted by stem cells, including but not limited to HGF, IL-1Ra, MMPs and TSG-6, could inhibit profibrotic effect of fibrogenic cytokines. Abbreviation: α-SMA: alpha-smooth muscle actin; HGF: hepatocyte growth factor; IFN-γ: interferon gamma; IGF-I: insulin-like growth factor I; IL-1: interleukin 1; IL-1Ra: interleukin 1 receptor antagonist; TSG-6: tumor necrosis factor-stimulated gene-6; MMP: matrix metalloproteinase; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor κB; PDGF: platelet-derived growth factor; PI3K: phosphoinositol 3-kinase; Ras: renal artery stenosis; TGF-β: transforming growth factor beta; TIMPs: tissue inhibitor of metalloproteinases; TNF-α: tumor necrosis factor alpha.
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