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Epicardial placement of human MSC-loaded fibrin sealant films for heart failure: Preclinical efficacy and mechanistic data.

ABSTRACT: Mesenchymal stromal cell (MSC) transplantation has been investigated as an advanced treatment of heart failure; however, further improvement of the therapeutic efficacy and mechanistic understanding are needed. Our previous study has reported that epicardial placement of fibrin sealant films incorporating rat amniotic membrane-derived (AM)-MSCs (MSC-dressings) could address limitations of traditional transplantation methods. To progress this finding toward clinical translation, this current study aimed to examine the efficacy of MSC-dressings using human AM-MSCs (hAM-MSCs) and the underpinning mechanism for myocardial repair. Echocardiography demonstrated that cardiac function and structure were improved in a rat ischemic cardiomyopathy model after hAM-MSC-dressing therapy. hAM-MSCs survived well in the rat heart, enhanced myocardial expression of reparative genes, and attenuated adverse remodeling. Copy number analysis by qPCR revealed that upregulated reparative genes originated from endogenous rat cells rather than hAM-MSCs. These results suggest hAM-MSC-dressing therapy stimulates a secondary release of paracrine factors from endogenous cells improving myocardial repair ("secondary paracrine effect"), and cardiac M2-like macrophages were identified as a potential cell source of repair. We demonstrated hAM-MSCs increased M2-like macrophages through not only enhancing M2 polarization but also augmenting their proliferation and migration capabilities via PGE₂, CCL2, and TGF-β1, resulting in enhanced cardiac function after injury.

SUBMITTER: Fields L

PROVIDER: S-EPMC8353205 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Epicardial placement of human MSC-loaded fibrin sealant films for heart failure: Preclinical efficacy and mechanistic data.

Fields Laura L Ito Tomoya T Kobayashi Kazuya K Ichihara Yuki Y Podaru Mihai-Nicolae MN Hussain Mohsin M Yamashita Kizuku K Machado Vanessa V Lewis-McDougall Fiona F Suzuki Ken K

Molecular therapy : the journal of the American Society of Gene Therapy 20210420 8

Mesenchymal stromal cell (MSC) transplantation has been investigated as an advanced treatment of heart failure; however, further improvement of the therapeutic efficacy and mechanistic understanding are needed. Our previous study has reported that epicardial placement of fibrin sealant films incorporating rat amniotic membrane-derived (AM)-MSCs (MSC-dressings) could address limitations of traditional transplantation methods. To progress this finding toward clinical translation, this current stud ...[more]

PMID: 33887461

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Project description:BackgroundThe anterior cruciate ligament (ACL) fails to heal after rupture, leading to joint instability and an increased risk of osteoarthritis. Mesenchymal stem/stromal cell (MSC) exosomes have reported wide-ranging therapeutic efficacy; however, their potential for augmenting ACL repair remains to be investigated.PurposeTo evaluate the use of MSC exosomes with fibrin sealant on biological augmentation of ACL healing after suture repair and their effects on ACL fibroblast functions.Study designControlled laboratory study.MethodsTwelve rabbit knees underwent ACL transection and suture repair. MSC exosome and fibrin composite (Exosome+Fibrin) or fibrin (Fibrin) alone was used to supplement the suture repair in 6 knees. ACL repair was assessed by magnetic resonance imaging at 6 and 12 weeks postoperatively and by histologic and immunohistochemical analyses at 12 weeks. To investigate the mechanisms through which MSC exosomes augment ACL repair, metabolic activity, proliferation, migration, and matrix synthesis assays were performed using the primary ACL fibroblasts. RNA sequencing was also performed to assess global gene expression changes in exosome-treated ACL fibroblasts.ResultsBased on magnetic resonance imaging findings, 5 of 6 Exosome+Fibrin-treated ACLs were completely or partially healed, as opposed to 5 of 6 Fibrin-treated ACLs appearing torn at 6 and 12 weeks postoperatively. Additionally, 4 of 6 Exosome+Fibrin-treated ACLs were isointense, as compared with 5 of 6 Fibrin-treated ACLs that were hyperintense, indicating improved remodeling and maturation of the repaired ACLs with Exosome+Fibrin treatment. Histologically, Exosome+Fibrin-treated ACLs showed more organized collagen fibers and abundant collagen deposition, with a high amount of collagen I and relatively lower amount of collagen III, which are consistent with the matrix structure and composition of the normal ACL. Cell culture studies using ACL fibroblasts showed that MSC exosomes enhanced proliferation, migration, and collagen synthesis and deposition, which are cellular processes relevant to ACL repair. Further gene set enrichment analysis revealed key pathways mediated by MSC exosomes in enhancing proliferation and migration while reducing matrix degradation of ACL fibroblasts.ConclusionThe combination of MSC exosomes and fibrin sealant (Exosome+Fibrin) applied to a suture repair enhanced the morphologic and histologic properties of the ACL in a rabbit model, and these improvements could be attributed to the augmented functions of ACL fibroblasts with exosome treatment.Clinical relevanceThis work supports the use of MSC exosomes in biological augmentation of ACL healing after suture repair.

Project description:BackgroundHeterologous fibrin sealant (HFS) consists of a fibrinogen-rich cryoprecipitate extracted from Bubalus bubalis buffalo blood and a thrombin-like enzyme purified from Crotalus durissus terrificus snake venom. This study evaluated the safety and immunogenicity of HFS, estimated the best dose, and assessed its preliminary efficacy in the treatment of chronic venous ulcers (CVU).MethodsA phase I/II non-randomized, single-arm clinical trial was performed on 31 participants, accounting for a total of 69 active CVUs. All ulcers were treated with HFS, essential fatty acid, and Unna boot for 12 weeks. The outcomes assessed were: (1) primary safety, immunogenicity analyses, and confirmation of the lowest safe dose; (2) secondary promising efficacy by analyzing the healing process. Immunogenicity was evaluated using the serum-neutralizing (IgM and IgG) and non-neutralizing (IgA and IgE) antibody techniques against the product. The immuno-detection of IgE class antibodies was assessed using dot-blot assay before and at the end of treatment. Positive samples on dot-blot assays were subsequently analyzed by western blotting to verify the results.ResultsNo severe systemic adverse events related to the use of HFS were observed. Local adverse events potentially related to treatment include ulcer pain (52%), peri-ulcer maceration (16%), peri-ulcer pruritus (12%), critical colonization (8%), peri-ulcer eczema (4%), the opening of new ulcers (4%), and increased ulcerated area 4%). Neutralizing and non-neutralizing antibodies did not show significant deviations at any of the evaluated time points. Blot assays showed that all patients presented negative immunological reactions, either before or after treatment, with the thrombin-like enzyme component. In addition, two participants showed a positive immunological reaction to the cryoprecipitate component, while another two were positive before and during treatment. Regarding the secondary outcomes of preliminary efficacy, a total healing and significant reduction of the area was observed in 47.5 and 22%, respectively. A qualitative improvement was observed in the wound beds of unhealed ulcers.ConclusionsThe investigational HFS bioproduct proved to be safe and non-immunogenic with a good preliminary efficacy for the treatment of CVU, according to the protocol and doses proposed. A multicentric phase III clinical trial will be necessary to verify these findings.

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Epicardial placement of human MSC-loaded fibrin sealant films for heart failure: Preclinical efficacy and mechanistic data.

Publications

Epicardial placement of human MSC-loaded fibrin sealant films for heart failure: Preclinical efficacy and mechanistic data.

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