Mesenchymal Stromal Cells Engineered to Produce IGF-I by Recombinant Adenovirus Ameliorate Liver Fibrosis in Mice

Abstract Background To investigate the heterogeneities of human umbilical cord mesenchymal stromal cells (HUCMSCs) derived from different donors and their therapeutic variations when applied to mouse liver fibrosis model. Methods The characteristics of HUCMSCs derived from multiple donors were comprehensively analyzed including expressions of surface markers, viability, growth curve, karyotype analysis, tumorigenicity, differentiation potentials, and immune regulation capability. Then, the HUCMSCs with distinct immunomodulatory effects were applied to treat mouse liver fibrosis and their therapeutic effects were observed. Results The HUCMSCs derived from multiple donors kept a high consistency in surface marker expressions, viability, growth curve, and tumorigenicity in nude mice but had robust heterogeneities in differentiation potentials and immune regulations. In addition, three HUCMSC lines applied to mice liver fibrosis model had different therapeutic outcomes, in line with individual immune regulation capability. Conclusion The HUCMSCs derived from different donors have individual heterogeneity, which potentially lead to distinct therapeutic outcomes in mouse liver fibrosis, indicating we could make use of the donor-variation of MSCs to screen out guaranteed general indicators of MSCs for specific diseases in further stromal cell therapy.

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Regulatory Effect of Mesenchymal Stromal Cells on the Development of Liver Fibrosis: Cellular and Molecular Mechanisms and Prospects for Clinical Application

Biology Bulletin Reviews ◽

10.1134/s2079086421010059 ◽

2021 ◽

Vol 11 (1) ◽

pp. 54-66

Author(s):

O. V. Payushina ◽

D. A. Tsomartova ◽

Y. V. Chereshneva ◽

M. Yu. Ivanova ◽

S. L. Kuznetsov

Keyword(s):

Liver Fibrosis ◽

Clinical Application ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Molecular Mechanisms ◽

Regulatory Effect

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Mesenchymal stromal cells prevent progression of liver fibrosis in a novel zebrafish embryo model

Scientific Reports ◽

10.1038/s41598-018-34351-5 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 2

Author(s):

Danny van der Helm ◽

Arwin Groenewoud ◽

Eveline S. M. de Jonge-Muller ◽

Marieke. C. Barnhoorn ◽

Mark J. A. Schoonderwoerd ◽

...

Keyword(s):

Liver Fibrosis ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Zebrafish Embryo

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Mesenchymal Stromal Cells Genetically Engineered To Overexpress Insulin-Like Growth Factor-1 Provide Paracrine Support for Cell-Based Erythropoietin Therapy of Chronic Renal Failure-Induced Anemia.

Blood ◽

10.1182/blood.v110.11.2598.2598 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2598-2598

Author(s):

Terrence Kucic ◽

Ian B. Copland ◽

Jessica Cuerquis ◽

Daniel L. Coutu ◽

Lorraine E. Chalifour ◽

...

Keyword(s):

Gene Therapy ◽

Renal Failure ◽

Chronic Renal Failure ◽

Growth Factor ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Mapk Pathway ◽

Insulin Like Growth Factor ◽

Igf I

Abstract Mesenchymal stromal cells (MSC) are a population of non-hematopoietic progenitors native to the bone marrow that are amenable to genetic engineering, making them attractive delivery vehicles for the in vivo production of therapeutic proteins, such as erythropoietin (Epo). We have previously demonstrated that MSC engineered to secrete Epo can be used for the long-term correction of renal failure-induced anemia [Eliopoulos et al., J Am Soc Nephrol. June 2006]. However, limited long-term transplanted cell survival compromises the efficacy of MSC-based gene therapy approaches. The current study provides evidence that co-implantation of MSC overexpressing Insulin-like growth factor-1 (IGF-I) improves MSC-based gene therapy of anemia by providing paracrine support to Epo-secreting MSC within a synthetic subcutaneous organoid. The IGF-I receptor was found to be expressed in murine MSC by RT-PCR, and protein expression was confirmed by immunoblot. We also demonstrated MSC MAPK pathway responsiveness to IGF-I stimulation in vitro and subsequent improvement of MSC survival following staurosporin-induced apoptosis. Murine MSC were transduced to overexpress either Epo or IGF-I (hereafter MSC-Epo and MSC-IGF) using retroviral vectors. MSC-Epo were subsequently admixed in a collagen matrix and implanted by subcutaneous injection in both naïve mice and a murine model of chronic renal failure, in combination with either MSC-IGF or null MSC. Mice receiving MSC-Epo in conjunction with MSC-IGF experienced a greater and significantly sustained elevation in hematocrit compared to control mice. In addition, mice co-implanted with MSC-IGF and MSC-Epo demonstrated a significant improvement in cardiac function compared to controls. In conclusion, cell-based gene therapy using co-implanted MSC-IGF represents a promising new strategy for the treatment of renal failure-induced anemia, as well as for the improvement of gene-enhanced MSC survival within implanted matrices.

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Mesenchymal stromal cells genetically engineered to overexpress IGF-I enhance cell-based gene therapy of renal failure-induced anemia

AJP Renal Physiology ◽

10.1152/ajprenal.00044.2008 ◽

2008 ◽

Vol 295 (2) ◽

pp. F488-F496 ◽

Cited By ~ 21

Author(s):

Terrence Kucic ◽

Ian B. Copland ◽

Jessica Cuerquis ◽

Daniel L. Coutu ◽

Lorraine E. Chalifour ◽

...

Keyword(s):

Gene Therapy ◽

Renal Failure ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Heart Function ◽

Collagen Matrix ◽

Genetically Engineered ◽

Functional Protein ◽

Igf I

We previously demonstrated that erythropoietin (EPO)-secreting mesenchymal stromal cells (MSC) can be used for the long-term correction of renal failure-induced anemia. The present study provides evidence that coimplantation of insulin-like growth factor I (IGF-I)-overexpressing MSC (MSC-IGF) improves MSC-based gene therapy of anemia by providing paracrine support to EPO-secreting MSC (MSC-EPO) within a subcutaneous implant. IGF-I receptor RNA expression in murine MSC was demonstrated by RT-PCR. Functional protein expression was confirmed by immunoblots and MSC responsiveness to IGF-I stimulation in vitro. IGF-I was also shown to improve MSC survival following staurosporin-induced apoptosis in vitro. A cohort of C57Bl/6 mice was rendered anemic by right kidney electrocoagulation and left nephrectomy. MSC-EPO were subsequently admixed in a bovine collagen matrix and implanted, in combination with MSC-IGF or MSC null, by subcutaneous injection in renal failure mice. In mice receiving MSC-EPO coimplanted with MSC-IGF, hematocrit elevation was greater and enhanced compared with control mice; heart function was also improved. MSC-IGF coimplantation, therefore, represents a promising new strategy for enhancing MSC survival within implanted matrices and for improving cell-based gene therapy of renal anemia.

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Involvement of hepatic macrophages in the antifibrotic effect of IGF-I-overexpressing mesenchymal stromal cells

Stem Cell Research & Therapy ◽

10.1186/s13287-016-0424-y ◽

2016 ◽

Vol 7 (1) ◽

Cited By ~ 15

Author(s):

Esteban Fiore ◽

Mariana Malvicini ◽

Juan Bayo ◽

Estanislao Peixoto ◽

Catalina Atorrasagasti ◽

...

Keyword(s):

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Antifibrotic Effect ◽

Hepatic Macrophages ◽

Igf I

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Remodeling of Human Osteochondral Defects via rAAV-Mediated Co-Overexpression of TGF-β and IGF-I from Implanted Human Bone Marrow-Derived Mesenchymal Stromal Cells

Journal of Clinical Medicine ◽

10.3390/jcm8091326 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1326

Author(s):

Stephanie Morscheid ◽

Jagadeesh Kumar Venkatesan ◽

Ana Rey-Rico ◽

Gertrud Schmitt ◽

Magali Cucchiarini

Keyword(s):

Bone Marrow ◽

Growth Factor ◽

Gene Transfer ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Human Bone ◽

Human Bone Marrow ◽

Human Model ◽

Cartilage Lesions ◽

Igf I

The application of chondrogenic gene sequences to human bone marrow-derived mesenchymal stromal cells (hMSCs) is an attractive strategy to activate the reparative activities of these cells as a means to enhance the processes of cartilage repair using indirect cell transplantation procedures that may improve the repopulation of cartilage lesions. In the present study, we examined the feasibility of co-delivering the highly competent transforming growth factor beta (TGF-β) with the insulin-like growth factor I (IGF-I) in hMSCs via recombinant adeno-associated virus (rAAV) vector-mediated gene transfer prior to implantation in a human model of osteochondral defect (OCD) ex vivo that provides a microenvironment similar to that of focal cartilage lesions. The successful co-overexpression of rAAV TGF-β/IGF-I in implanted hMSCs promoted the durable remodeling of tissue injury in human OCDs over a prolonged period of time (21 days) relative to individual gene transfer and the control (reporter lacZ gene) treatment, with enhanced levels of cell proliferation and matrix deposition (proteoglycans, type-II collagen) both in the lesions and at a distance, while hypertrophic, osteogenic, and catabolic processes could be advantageously delayed. These findings demonstrate the value of indirect, progenitor cell-based combined rAAV gene therapy to treat human focal cartilage defects in a natural environment as a basis for future clinical applications.

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