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Boosting therapeutic efficacy of mesenchymal stem cells in pulmonary fibrosis: The role of genetic modification and preconditioning strategies.

ABSTRACT: Pulmonary fibrosis (PF) is the end stage of severe lung diseases, in which the lung parenchyma is replaced by fibrous scar tissue. The result is a remarkable reduction in pulmonary compliance, which may lead to respiratory failure and even death. Idiopathic pulmonary fibrosis (IPF) is the most prevalent form of PF, with no reasonable etiology. However, some factors are believed to be behind the etiology of PF, including prolonged administration of several medications (e.g., bleomycin and amiodarone), environmental contaminant exposure (e.g., gases, asbestos, and silica), and certain systemic diseases (e.g., systemic lupus erythematosus). Despite significant developments in the diagnostic approach to PF in the last few years, efforts to find more effective treatments remain challenging. With their immunomodulatory, anti-inflammatory, and anti-fibrotic properties, stem cells may provide a promising approach for treating a broad spectrum of fibrotic conditions. However, they may lose their biological functions after long-term in vitro culture or exposure to harsh in vivo situations. To overcome these limitations, numerous modification techniques, such as genetic modification, preconditioning, and optimization of cultivation methods for stem cell therapy, have been adopted. Herein, we summarize the previous investigations that have been designed to assess the effects of stem cell preconditioning or genetic modification on the regenerative capacity of stem cells in PF.

SUBMITTER: Mehrabani M

PROVIDER: S-EPMC10440137 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Boosting therapeutic efficacy of mesenchymal stem cells in pulmonary fibrosis: The role of genetic modification and preconditioning strategies.

Mehrabani Mehrnaz M Mohammadyar Sohaib S Rajizadeh Mohammad Amin MA Bejeshk Mohammad Abbas MA Ahmadi Bahareh B Nematollahi Mohammad Hadi MH Mirtajaddini Goki Maryamossadat M Bahrampour Juybari Kobra K Amirkhosravi Arian A

Iranian journal of basic medical sciences 20230101 9

Pulmonary fibrosis (PF) is the end stage of severe lung diseases, in which the lung parenchyma is replaced by fibrous scar tissue. The result is a remarkable reduction in pulmonary compliance, which may lead to respiratory failure and even death. Idiopathic pulmonary fibrosis (IPF) is the most prevalent form of PF, with no reasonable etiology. However, some factors are believed to be behind the etiology of PF, including prolonged administration of several medications (e.g., bleomycin and amiodar ...[more]

PMID: 37605719

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is an age-related disease with no cure. Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy for IPF treatment. Nevertheless, MSCs derived from patients with IPF (IPF-MSCs) become senescent, thereby reducing their beneficial effects in IPF. MicroRNAs (miRNAs) mediate the senescence of MSCs, but the underlying mechanisms are not fully understood. We investigated the mechanisms by which miR-199a-5p regulates IPF-MSC senescence and whether its inhibition could rejuvenate IPF-MSCs and enhance their therapeutic efficacy.MethodsControl-MSCs and IPF-MSCs were isolated from the adipose tissue of age-matched healthy and IPF donors, respectively. Cell senescence was examined by senescence-associated β-galactosidase (SA-β-gal) staining. The level of miR-199a-5p was measured by RT-PCR. Autophagy was determined using a transmission electron microscope (TEM). The therapeutic efficacy of anti-miR-199a-5p-IPF-MSCs was assessed using a mouse model of bleomycin-induced lung fibrosis.ResultsDespite similar surface makers, IPF-MSCs exhibited increased cellular senescence and decreased proliferative capacity compared with control-MSCs. The expression of miR-199a-5p was significantly enhanced in the serum of IPF patients and IPF-MSCs compared with that of healthy donors and control-MSCs. The upregulation of miR-199a-5p induced senescence of control-MSCs, whereas the downregulation rescued IPF-MSC senescence. Mechanistically, miR-155-5p suppressed autophagy of MSCs via the AMPK signaling pathway by downregulating the expression of Sirtuin 1(Sirt1), resulting in cellular senescence. Accordingly, miR-155-5p inhibition promoted autophagy and ameliorated IPF-MSC senescence by activating the Sirt1/AMPK signaling pathway. Compared with IPF-MSCs, the transplantation of anti-miR-199a-5p-IPF-MSCs increased the ability to prevent progression of pulmonary fibrosis in bleomycin-treated mice.ConclusionsOur study shows that miR-199a-5p regulates MSC senescence in patients with IPF by regulating the Sirt1/AMPK signaling pathway and miR-199a-5p is a novel target to rejuvenate IPF-MSCs and enhance their beneficial effects.

Project description:BackgroundMesenchymal stem cells (MSCs) repair injured tissue in a paracrine manner. To enhance their therapeutic properties, preconditioning with various factors has been researched. We have previously showed that MSCs cultured in serum-free medium (SF-MSCs) promote their immunosuppressive ability, thereby enhancing their anti-fibrotic effect. Here, we examined whether serum-free medium and hypoxic preconditioning synergistically enhance the therapeutic effects of MSCs on renal fibrosis in rats with ischemia-reperfusion injury (IRI).MethodsSF-MSCs were incubated under 1% O2 conditions (hypo-SF-MSCs) or 21% O2 conditions (normo-SF-MSCs) for 24 h before collection. After IRI procedure, hypo-SF-MSCs or normo-SF-MSCs were injected through the abdominal aorta. At 7 or 21 days post-injection, the rats were killed and their kidneys were collected to evaluate inflammation and fibrosis. In in vitro experiments, we investigated whether hypo-SF-MSCs enhanced secretion of anti-fibrotic humoral factors using transforming growth factor (TGF)-β1-stimulated HK-2 cells incubated with conditioned medium from hypo-SF-MSCs or normo-SF-MSCs.ResultsNormo-SF-MSCs showed attenuation of senescence, which increased their proliferative capacity. Although no significant difference in cellular senescence was found between normo-SF-MSCs and hypo-SF-MSCs, hypo-SF-MSCs further increased their proliferative capacity compared with normo-SF-MSCs. Additionally, administration of hypo-SF-MSCs more strongly ameliorated renal fibrosis than that of normo-SF-MSCs. Moreover, although hypo-SF-MSCs strongly attenuated infiltration of inflammatory cells compared with the control rats, which were treated with PBS, this attenuation was almost equal between normo-SF-MSCs and hypo-SF-MSCs. In vitro experiments revealed that hypo-SF-MSCs more significantly inhibited transforming growth factor (TGF)-β/Smad signaling compared with normo-SF-MSCs. Moreover, hypoxic preconditioning increased hepatocyte growth factor (HGF) secretion even under serum-free conditions, whereas knockdown of HGF in hypo-SF-MSCs attenuated inhibition of TGF-β/Smad signaling.ConclusionsThese results indicate that administration of ex vivo-expanded, hypoxia-preconditioned SF-MSCs may be a useful cell therapy to prevent renal fibrosis.

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Boosting therapeutic efficacy of mesenchymal stem cells in pulmonary fibrosis: The role of genetic modification and preconditioning strategies.

Publications

Boosting therapeutic efficacy of mesenchymal stem cells in pulmonary fibrosis: The role of genetic modification and preconditioning strategies.

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