Recellularization of xenograft heart valves reduces the xenoreactive immune response in an in vivo rat model

2021 ◽  
Author(s):  
Sabin J Bozso ◽  
Jimmy J H Kang ◽  
Ryaan EL-Andari ◽  
Nicholas Fialka ◽  
Lin Fu Zhu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Stem Cell ◽  
Aortic Valve ◽  
Mesenchymal Stem Cell ◽  
Rat Model ◽  
Cell Infiltration ◽  
Immunoglobulin Production ◽  
Autologous Grafts

Abstract OBJECTIVES Our aim was to address the role of autologous mesenchymal stem cell recellularization of xenogenic valves on the activation of the xenoreactive immune response in an in vivo rat model. METHODS Explanted aortic valve constructs from female Hartley guinea pigs were procured and decellularized, followed by recellularization with autologous Sprague-Dawley rat mesenchymal stem cells. Aortic valve xenografts were then implanted into the infrarenal aorta of recipient rats. Grafts were implanted as either autologous grafts, non-decellularized (NGP), decellularized and recellularized xenografts (RGP). Rats were euthanized after 7 and 21 days and exsanguinated and the grafts were explanted. RESULTS The NGP grafts demonstrated significant burden of granulocytes (14.3 cells/HPF) and CD3+ T cells (3.9 cells/HPF) compared to the autologous grafts (2.1 granulocytes/HPF and 0.72 CD3+ T cells/HPF) after 7 days. A lower absolute number of infiltrating granulocytes (NGP vs autologous, 6.4 vs 2.4 cells/HPF) and CD3+ T cells (NGP vs autologous, 2.8 vs 0.8 cells/HPF) was seen after 21 days. Equivalent granulocyte cell infiltration in the RGP grafts (2.4 cells/HPF) compared to the autologous grafts (2.1 cells/HPF) after 7 and 21 days (2.8 vs 2.4 cells/HPF) was observed. Equivalent CD3+ T-cell infiltration in the RGP grafts (0.63 cells/HPF) compared to the autologous grafts (0.72 cells/HPF) after 7 and 21 days (0.7 vs 0.8 cells/HPF) was observed. Immunoglobulin production was significantly greater in the NGP grafts compared to the autologous grafts at 7 (123.3 vs 52.7 mg/mL) and 21 days (93.3 vs 71.6 mg/mL), with a similar decreasing trend in absolute production. Equivalent immunoglobulin production was observed in the RGP grafts compared to the autologous grafts at 7 (40.8 vs 52.7 mg/mL) and 21 days (29.5 vs 71.6 mg/mL). CONCLUSIONS Autologous mesenchymal stem cell recellularization of xenogenic valves reduces the xenoreactive immune response in an in vivo rat model and may be an effective approach to decrease the progression of xenograft valve dysfunction.

Abstract 226: Recellularization of Xenograft Heart Valves Reduces the Xenoreactive Immune Response in an In Vivo Rat Model

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Sabin J Bozso ◽  
Ryaan EL-Andari ◽  
Lin Fu Zhu ◽  
Benjamin Adam ◽  
Michael C Moon ◽  
...  
Keyword(s):  
Immune Response ◽  
Aortic Valve ◽  
Guinea Pig ◽  
Rat Model ◽  
Serum Immunoglobulin ◽  
Total Serum ◽  
Sprague Dawley ◽  
Cellular Infiltrate ◽  
Immunoglobulin Production

Background: Current xenograft valve constructs provoke an intense immune response that may lead to valve dysfunction. Our aim was to address the role of autologous mesenchymal stem cell (MSC) recellularization of xenogenic valves on the activation of the xenoreactive immune response in an in-vivo rat model. Methods: Explanted aortic valve constructs from female Hartley guinea pigs were procured and decellularized, followed by recellularization with syngeneic Sprague-Dawley rat MSCs. The recellularized aortic valve xenografts were then implanted into the infrarenal aorta of recipient female Sprague-Dawley rats. Grafts were implanted as either syngeneic grafts, non-decellularized (fresh), decellularized and recellularized xenografts. Rats were euthanized after 7-days, exsanguinated and the grafts explanted. Total serum immunoglobulin was quantified and histological analysis perfomed to analyze the immune response. Results: Overall survival to endpoint was significantly lower in the decellularized xenograft group (67%; 4/6), compared to fresh (100%; 6/6) and recellularized grafts (100%; 6/6). Similarly grafts in the decellularized group were more likely to have completely thrombosed (50%; 2/4), compared to fresh (33%; 2/6) and recellularized grafts (0%; 0/6). Decellularized guinea pig xenografts, when implanted into rats in-vivo , result in significantly reduced total serum immunoglobulin production and significantly reduced graft cellular infiltrate when compared to fresh xenografts. Moreover, when decellularized guinea pig xenografts were recellularized with syngeneic rat MSCs there was an additional decrease in total serum immunoglobulin production and graft cellular infiltrate when compared to both fresh and decellularized xenografts. Importantly, recellularized guinea pig xenografts had an equivalent total immunoglobulin production and graft cellular infiltrate when compared to syngeneic rat aortic valve controls. Conclusions: Autologous MSC recellularization of xenogenic valves reduces the xenoreactive immune response in an in-vivo rat model and may be an effective approach to decrease the progression of xenograft valve dysfunction.

scholarly journals Dimethyloxaloylglycine-stimulated human bone marrow mesenchymal stem cell-derived exosomes enhance bone regeneration through angiogenesis by targeting the AKT/mTOR pathway

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Bo Liang ◽  
Jia-Ming Liang ◽  
Jia-Ning Ding ◽  
Jia Xu ◽  
Jian-Guang Xu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Bone Regeneration ◽  
Rat Model ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Mtor Pathway ◽  
Calvarial Defect

Abstract Background Mesenchymal stem cell (MSC)-derived exosomes have been recognized as new candidate agents for treating critical-sized bone defects; they promote angiogenesis and may be an alternative to cell therapy. In this study, we evaluated whether exosomes derived from bone marrow-derived MSCs (BMSCs) preconditioned with a low dose of dimethyloxaloylglycine (DMOG), DMOG-MSC-Exos, exert superior proangiogenic activity in bone regeneration and the underlying mechanisms involved. Methods To investigate the effects of these exosomes, scratch wound healing, cell proliferation, and tube formation assays were performed in human umbilical vein endothelial cells (HUVECs). To test the effects in vivo, a critical-sized calvarial defect rat model was established. Eight weeks after the procedure, histological/histomorphometrical analysis was performed to measure bone regeneration, and micro-computerized tomography was used to measure bone regeneration and neovascularization. Results DMOG-MSC-Exos activated the AKT/mTOR pathway to stimulate angiogenesis in HUVECs. This contributed to bone regeneration and angiogenesis in the critical-sized calvarial defect rat model in vivo. Conclusions Low doses of DMOG trigger exosomes to exert enhanced proangiogenic activity in cell-free therapeutic applications.

scholarly journals Human umbilical cord mesenchymal stem cell-derived exosomal miR-27b attenuates subretinal fibrosis via suppressing epithelial–mesenchymal transition by targeting HOXC6

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dongli Li ◽  
Junxiu Zhang ◽  
Zijia Liu ◽  
Yuanyuan Gong ◽  
Zhi Zheng
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Umbilical Cord ◽  
Mechanism Of Action ◽  
Epithelial Mesenchymal Transition ◽  
Human Umbilical Cord ◽  
Mesenchymal Transition ◽  
Rpe Cells ◽  
Subretinal Fibrosis

Abstract Background and aim Subretinal fibrosis resulting from neovascular age-related macular degeneration (nAMD) is one of the major causes of serious and irreversible vision loss worldwide, and no definite and effective treatment exists currently. Retinal pigmented epithelium (RPE) cells are crucial in maintaining the visual function of normal eyes and its epithelial–mesenchymal transition (EMT) is associated with the pathogenesis of subretinal fibrosis. Stem cell-derived exosomes have been reported to play a crucial role in tissue fibrosis by transferring their molecular contents. This study aimed to explore the effects of human umbilical cord-derived mesenchymal stem cell exosomes (hucMSC-Exo) on subretinal fibrosis in vivo and in vitro and to investigate the anti-fibrotic mechanism of action of hucMSC-Exo. Methods In this study, human umbilical cord-derived mesenchymal stem cells (hucMSCs) were successfully cultured and identified, and exosomes were isolated from the supernatant by ultracentrifugation. A laser-induced choroidal neovascularization (CNV) and subretinal fibrosis model indicated that the intravitreal administration of hucMSC-Exo effectively alleviated subretinal fibrosis in vivo. Furthermore, hucMSC-Exo could efficaciously suppress the migration of retinal pigmented epithelial (RPE) cells and promote the mesenchymal–epithelial transition by delivering miR-27b-3p. The latent binding of miR-27b-3p to homeobox protein Hox-C6 (HOXC6) was analyzed by bioinformatics prediction and luciferase reporter assays. Results This study showed that the intravitreal injection of hucMSC-Exo effectively ameliorated laser-induced CNV and subretinal fibrosis via the suppression of epithelial–mesenchymal transition (EMT) process. In addition, hucMSC-Exo containing miR-27b repressed the EMT process in RPE cells induced by transforming growth factor-beta2 (TGF-β2) via inhibiting HOXC6 expression. Conclusions The present study showed that HucMSC-derived exosomal miR-27b could reverse the process of EMT induced by TGF-β2 via inhibiting HOXC6, indicating that the exosomal miR-27b/HOXC6 axis might play a vital role in ameliorating subretinal fibrosis. The present study proposed a promising therapeutic agent for treating ocular fibrotic diseases and provided insights into the mechanism of action of hucMSC-Exo on subretinal fibrosis.

In vivo study of the angiogenesis potential of bone marrow-derived mesenchymal stem cell aggregates in their niche like environment

2021 ◽  
pp. 039139882110255
Author(s):  
Sara Anajafi ◽  
Azam Ranjbar ◽  
Monireh Torabi-Rahvar ◽  
Naser Ahmadbeigi
Keyword(s):  
Tissue Engineering ◽  
Bone Marrow ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Cultured Cells ◽  
Morphological Evidence ◽  
Cell Aggregates ◽  
Plla Scaffold ◽  
Significant Difference

Background: Sufficient blood vessel formation in bioengineered tissues is essential in order to keep the viability of the organs. Impaired development of blood vasculatures results in failure of the implanted tissue. The cellular source which is seeded in the scaffold is one of the crucial factors involved in tissue engineering methods. Materials and methods: Considering the notable competence of Bone Marrow derived Mesenchymal Stem Cell aggregates for tissue engineering purposes, in this study BM-aggregates and expanded BM-MSCs were applied without any inductive agent or co-cultured cells, in order to investigate their own angiogenesis potency in vivo. BM-aggregates and BM-MSC were seeded in Poly-L Lactic acid (PLLA) scaffold and implanted in the peritoneal cavity of mice. Result: Immunohistochemistry results indicated that there was a significant difference ( p < 0.050) in CD31+ cells between PLLA scaffolds contained cultured BM-MSC; PLLA scaffolds contained BM-aggregates and empty PLLA. According to morphological evidence, obvious connections with recipient vasculature and acceptable integration with surroundings were established in MSC and aggregate-seeded scaffolds. Conclusion: Our findings revealed cultured BM-MSC and BM-aggregates, capacity in order to develop numerous connections between PLLA scaffold and recipient’s vasculature which is crucial to the survival of tissues, and considerable tendency to develop constructs containing CD31+ endothelial cells which can contribute in vessel’s tube formation.

scholarly journals Autophagy-Mediated Activation of Mucosal-Associated Invariant T Cells Driven by Mesenchymal Stem Cell-Derived IL-15

2021 ◽  
Author(s):  
Guiwen Ye ◽  
Peng Wang ◽  
Zhongyu Xie ◽  
Qian Cao ◽  
Jinteng Li ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Invariant T Cells
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