Immunomodulation by systemic administration of human-induced pluripotent stem cell-derived mesenchymal stromal cells to enhance the therapeutic efficacy of cell-based therapy for treatment of myocardial infarction

Sun, Si-Jia; Lai, Wing‐Hon; Yu, Jiang; Zhen, Zhe; Wei, Rui; Lian, Qizhou; Liao, Song-Yan; Tse, Hung‐Fat

doi:10.7150/thno.46119

Cited by 38 publications

(31 citation statements)

References 18 publications

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“…Therefore, inhibiting the early inflammatory response of tendon injury is beneficial to early healing. Recent studies reported that MSCs can elicit immunoregulatory responses by modulating the pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophage polarization, inducing regulatory T cells, and producing anti-inflammatory cytokines [ 38 , 39 ]. Considering exosomes are the main substances used by MSCs to exert their effectiveness, we hypothesized that exosomes would recapitulate the immunomodulatory effects of their parent cells.…”

Section: Discussionmentioning

confidence: 99%

Adipose-derived mesenchymal stromal cell-derived exosomes promote tendon healing by activating both SMAD1/5/9 and SMAD2/3

et al. 2021

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Background The use of adipose-derived mesenchymal stromal cell-derived exosomes (ADSC-Exos) may become a new therapeutic method in biomedicine owing to their important role in regenerative medicine. However, the role of ADSC-Exos in tendon repair has not yet been evaluated. Therefore, we aimed to clarify the healing effects of ADSC-Exos on tendon injury. Methods The adipose-derived mesenchymal stromal cells (ADSCs) and tendon stem cells (TSCs) were isolated from the subcutaneous fat and tendon tissues of Sprague-Dawley rats, respectively, and exosomes were isolated from ADSCs. The proliferation and migration of TSCs induced by ADSC-Exos were analyzed by EdU, cell scratch, and transwell assays. We used western blot to analyze the tenogenic differentiation of TSCs and the role of the SMAD signaling pathways. Then, we explored a new treatment method for tendon injury, combining exosome therapy with local targeting using a biohydrogel. Immunofluorescence and immunohistochemistry were used to detect the expression of inflammatory and tenogenic differentiation after tendon injury, respectively. The quality of tendon healing was evaluated by hematoxylin-eosin (H&E) staining and biomechanical testing. Results ADSC-Exos could be absorbed by TSCs and promoted the proliferation, migration, and tenogenic differentiation of these cells. This effect may have depended on the activation of the SMAD2/3 and SMAD1/5/9 pathways. Furthermore, ADSC-Exos inhibited the early inflammatory reaction and promoted tendon healing in vivo. Conclusions Overall, we demonstrated that ADSC-Exos contributed to tendon regeneration and provided proof of concept of a new approach for treating tendon injuries.

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Section: Discussionmentioning

confidence: 99%

Adipose-derived mesenchymal stromal cell-derived exosomes promote tendon healing by activating both SMAD1/5/9 and SMAD2/3

et al. 2021

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“…There is evidence that intravenous, intracoronary, or intramyocardial administration of MSCs can improve LV function in an MI model ( Bagno et al., 2018 ; Hu et al., 2016 ; Liao et al., 2019 ). Moreover, our previous study showed that pre-transplantation systemic intravenous administration of MSCs improved retention and therapeutic efficacy of intramyocardially transplanted exogenous cells ( Sun et al., 2021 ).…”

Section: Main Textmentioning

confidence: 99%

“…Recently, our group has investigated the immunomodulatory effect of human iPSC (hiPSC)-MSCs on improving the survival and therapeutic efficacy of cells following intramyocardial transplantation into a mouse model of MI ( Sun et al., 2021 ). Our results showed that pre-transplantation systemic administration of hiPSC-MSCs increased systemic regulatory T cell (Treg) activation, decreased the number of splenic natural killer (NK) cells and inflammation, enhanced survival of transplanted hiPSC-MSCs and hiPSC-cardiomyocytes following intramyocardial transplantation, and improved the therapeutic efficacy at 4 weeks post MI.…”

Section: Main Textmentioning

confidence: 99%

Mesenchymal stromal cell-derived exosomes in cardiac regeneration and repair

Sun

Wei

et al. 2021

Stem Cell Reports

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Mesenchymal stromal cell (MSC)-derived exosomes play a promising role in regenerative medicine. Their trophic and immunomodulatory potential has made them a promising candidate for cardiac regeneration and repair. Numerous studies have demonstrated that MSC-derived exosomes can replicate the antiinflammatory, anti-apoptotic, and pro-angiogenic and antifibrotic effects of their parent cells and are considered a substitute for cell-based therapies. In addition, their lower tumorigenic risk, superior immune tolerance, and superior stability compared with their parent stem cells make them an attractive option in regenerative medicine. The therapeutic effects of MSC-derived exosomes have consequently been evaluated for application in cardiac regeneration and repair. In this review, we summarize the potential mechanisms and therapeutic effects of MSC-derived exosomes in cardiac regeneration and repair and provide evidence to support their clinical application.

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“…Human iMSCs were differentiated from human induced pluripotent stem cell (hiPSC) line IMR90-iPSCs (WiCell Research Institute, Madison, WI, USA) as previously described [6,18]. Briefly, hiPSCs were cultured in MSC differentiation medium which consists of 10% fetal bovine serum (FBS), 5 ng/mL basic fibroblast growth factor (bFGF; AF-100-18B, Peprotech), 5 ng/mL epidermal growth factor (EGF; AF-100-15, Peprotech) and 55 uM 2-mercaptoethanol (Gibco, 21985023).…”

Section: Preparation and Characterization Of Imscs And Umscsmentioning

confidence: 99%

Conditioned medium from induced pluripotent stem cell-derived mesenchymal stem cells accelerates cutaneous wound healing through enhanced angiogenesis

et al. 2021

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Background Mesenchymal stem cells (MSCs) can improve cutaneous wound healing via the secretion of growth factors. However, the therapeutic efficacy of MSCs varies depending upon their source. Induced pluripotent stem cells are emerging as a promising source of MSCs with the potential to overcome several limitations of adult MSCs. This study compared the effectiveness of conditioned medium of MSCs derived from induced pluripotent stem cells (iMSC-CdM) with that derived from umbilical cord MSCs (uMSC-CdM) in a mouse cutaneous wound healing model. We also investigated the mechanisms of protection. Methods The iMSC-CdM or uMSC-CdM were topically applied to mice cutaneous wound model. The recovery rate, scar formation, inflammation and angiogenesis were measured. We compared angiogenesis cytokine expression between iMSC-CdM and uMSC-CdM and their protective effects on human umbilical vein endothelial cells (HUVECs) under H2O2-induced injury. The effects of iMSC-CdM on energy metabolism, mitochondria fragmentation and apoptosis were measured. Results Topical application of iMSC-CdM was superior to the uMSC-CdM in accelerating wound closure and enhancing angiogenesis. Expression levels of angiogenetic cytokines were higher in iMSC-CdM than they were in uMSC-CdM. The iMSC-CdM protected HUVECs from H2O2 induced injury more effectively than uMSC-CdM did. Administration of iMSC-CdM stimulated HUVEC proliferation, tube formation and energy metabolism via the ERK pathway. Mechanistically, iMSC-CdM inhibited H2O2-induced mitochondrial fragmentation and apoptosis of HUVECs. Conclusion Collectively, these findings indicate that iMSC-CdM is more effective than uMSC-CdM in treating cutaneous wounds, and in this way, iMSC-CdM may serve as a more constant and sustainable source for cell-free therapeutic approach. Graphical abstract

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Immunomodulation by systemic administration of human-induced pluripotent stem cell-derived mesenchymal stromal cells to enhance the therapeutic efficacy of cell-based therapy for treatment of myocardial infarction

Cited by 38 publications

References 18 publications

Adipose-derived mesenchymal stromal cell-derived exosomes promote tendon healing by activating both SMAD1/5/9 and SMAD2/3

Adipose-derived mesenchymal stromal cell-derived exosomes promote tendon healing by activating both SMAD1/5/9 and SMAD2/3

Mesenchymal stromal cell-derived exosomes in cardiac regeneration and repair

Conditioned medium from induced pluripotent stem cell-derived mesenchymal stem cells accelerates cutaneous wound healing through enhanced angiogenesis

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