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Updated: May 13, 2026
Stem Cell Transplantation in an in vitro Simulated Ischemia/Reperfusion Model
Published on: November 5, 2011
Effect of mesenchymal stem cells on Doxorubicin-induced fibrosis
Simin Mohammadi Gorji1, Abbas Ali Karimpor Malekshah, Mohammad Baghere Hashemi-Soteh
11. Department of Biology, Islamic Azad University, Science and Research Branch, Tehran, Iran.
Objective:
The aim of this study was to test the effect of intravenous injection of mesenchymal stem cells (MSCs) on doxorubicin (DOX)-induced fibrosis in the heart. We investigated the mechanisms that possibly mediate this effect.
Materials And Methods:
In this experimental study, fibrosis in the myocardium of adult male Wistar rats (weights 180-200 g, 9-10 weeks of age, total n=30) was created by DOX administration. DOX (2.5 mg/kg) was administered intraperitoneally 3 times a week, for a total dose of 15 mg/kg over a period of 2 weeks. MSCs from Wistar rats were separated and cultured in Dulbecco's modified eagle medium (DMEM). The condition medium (CM) which contained factors secreted by MSCs was also collected from MSCs cultured in serum-free DMEM. Two weeks after the first injection of DOX, MSCs, CM and standard medium (SM) were transplanted via intravenous injection. Four weeks after transplantation, histological (Masson's trichrome staining for fibrosis detection) and molecular [real-time polymerase chain reaction (RT-PCR)] analyses were conducted. In addition, insulin-like growth factor (IGF-1) and hepatocyte growth factor (HGF) in the CM were measured with an enzyme-linked immunosorbent assay (ELISA). For immunosuppressive treatment, cyclosporine A was given (intraperitoneally, 5 mg/kg/day) starting on the day of surgery until the end of study in all groups. Fibrosis rate and relative gene expression were compared by analysis of variance (ANOVA) and post-Tukey's test. HGF and (IGF-1 in the CM were analyzed by independent sample t test. P<0.01 was considered statistically significant.
Results:
Our data demonstrated that intravenously transplanted MSCs and CM significantly reduced fibrosis and significantly increased Bcl-2 expression levels in the myocardium compared to the DOX group (p<0.01). However, there was no significant difference between Bax expression levels in these groups. In addition, secretion of HGF and IGF-1 was detected in the CM (p<0.01).
Conclusion:
We conclude that intravenous transplantation of MSCs and CM can attenuate myocardial fibrosis and increase Bcl-2 expression. This may be mediated by paracrine signaling from MSCs via anti-fibrotic and anti-apoptotic factors such as HGF and IGF-1.
Insights
Mesenchymal stem cells (MSCs) and their conditioned medium (CM) effectively reduced doxorubicin-induced heart fibrosis in rats. This therapeutic effect is linked to paracrine signaling, involving anti-fibrotic and anti-apoptotic factors like HGF and IGF-1.
Area of Science:
- Regenerative Medicine
- Cardiovascular Research
- Stem Cell Therapy
Background:
- Doxorubicin (DOX) is a potent chemotherapy agent known to induce cardiotoxicity and myocardial fibrosis.
- Current therapeutic strategies for DOX-induced cardiotoxicity are limited, highlighting the need for novel treatment approaches.
- Mesenchymal stem cells (MSCs) have demonstrated potential in tissue repair and regeneration through paracrine mechanisms.
Purpose of the Study:
- To evaluate the efficacy of intravenous mesenchymal stem cells (MSCs) in attenuating doxorubicin (DOX)-induced myocardial fibrosis.
- To investigate the underlying mechanisms, including the role of paracrine factors secreted by MSCs.
- To assess the impact of MSCs and their conditioned medium (CM) on cardiac fibrosis markers and apoptosis-related gene expression.
Main Methods:
- Adult male Wistar rats were subjected to DOX administration to induce myocardial fibrosis.
- Intravenous transplantation of MSCs, MSC-conditioned medium (CM), or standard medium was performed.
- Histological analysis (Masson's trichrome staining) and molecular analysis (RT-PCR) were conducted to assess fibrosis and gene expression (Bcl-2, Bax).
- Enzyme-linked immunosorbent assay (ELISA) was used to quantify hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) in CM.
Main Results:
- Intravenous MSCs and CM significantly reduced myocardial fibrosis in DOX-treated rats compared to the control group (p<0.01).
- Bcl-2 expression levels were significantly increased in the myocardium following MSC and CM treatment, indicating reduced apoptosis (p<0.01).
- HGF and IGF-1 were detected in the CM, suggesting their involvement in the therapeutic effects.
Conclusions:
- Intravenous transplantation of MSCs and CM effectively attenuates doxorubicin-induced myocardial fibrosis.
- The observed cardioprotective effects are likely mediated by paracrine signaling, involving anti-fibrotic and anti-apoptotic factors such as HGF and IGF-1.
- MSC-based therapy holds promise for managing chemotherapy-induced cardiotoxicity.
