Abstract
Therapeutic applications of tissue-derived mesenchymal stem cells (MSCs) are hindered by their limited expansion ability and variation across donors. Human induced pluripotent stem cell (iPSC)-derived MSCs show greater expandability and therefore offer potential for use in tissue repair therapies. Here we explored the regenerative effects of iPSC-MSCs and the mechanisms by which iPSC-MSCs promote mucosal healing via tumor necrosis factor-α-stimulated gene 6 (TSG-6) in mouse models of inflammatory bowel disease (IBD). Human iPSCs were induced to differentiate into MSCs following a clinically compliant protocol. The iPSC-MSC treatment promoted mucosal healing in colitic mice, accompanied by increased epithelial cell proliferation, CD44-positive cells, and Lgr5-positive cells. TSG-6 knockdown in iPSC-MSCs or blocking of hyaluronan–CD44 interactions by PEP-1 abrogated the therapeutic effects of iPSC-MSCs, whereas use of recombinant TSG-6 showed therapeutic effects similar to those of iPSC-MSCs. A mouse or patient-derived organoid culture system was developed. Organoids co-cultured with iPSC-MSCs showed increased epithelial cell proliferation, CD44-positive cells, and Lgr5-positive cells, which was abolished by TSG-6 knockdown. TSG-6-induced promoting effects in organoids were dependent on Akt activation and abrogated by the anti-CD44 antibody or MK2206. In conclusion, iPSC-MSCs promoted epithelial cell proliferation to accelerate mucosal healing in a murine colitis model via TSG-6 through hyaluronan–CD44 interactions in an Akt-dependent manner, demonstrating a patient-specific “off-the-shelf” format for IBD treatment.
Highlights
Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis, are chronic relapsing diseases characterized by persistent intestinal inflammation of IBD patients treated with conventional therapies, including corticosteroids, immunomodulators, and even biologic agents, show mucosal healing[3]
We found that tumor necrosis factor-αstimulated gene 6 (TSG-6) released by induced pluripotent stem cell (iPSC)-mesenchymal stem cells (MSCs) plays an essential role in determining the therapeutic effects of iPSC-MSCs on murine colitis by stimulating intestinal epithelial proliferation through interactions between CD44 and hyaluronic acid (HA)
We found that a single intraperitoneal injection of iPSC-MSCs (2 × 106 cells per mouse) significantly improved clinical parameters in colitic mice (T-iPS group) such as body weight and colon length when compared to colitic mice that were administered phosphate-buffered saline (PBS) (T-PBS group) (Fig. 1a, b)
Summary
Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis, are chronic relapsing diseases characterized by persistent intestinal inflammation of IBD patients treated with conventional therapies, including corticosteroids, immunomodulators, and even biologic agents, show mucosal healing[3]. Conventional therapies to treat IBD are based on immune suppression; new therapeutic strategies to promote mucosal regeneration are needed[4,5]. MSCs are hypoimmunogenic, and the use of allogeneic MSCs is usually safe[15,16]. Despite their promising therapeutic effects, tissue-derived MSCs have several weaknesses, such as their limited proliferative potential, standardization difficulty, loss of differentiation capacity, and decreased therapeutic efficacy during expansion[17]. Because we observed repair of other tissues in response to iPSCMSCs, we further evaluated the therapeutic effects of human iPSC-MSCs on mucosal healing in mouse models of IBD in the present study
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