Table 1.
Summary of the methods and experimental findings on using mesenchymal stem cell therapy for DOX-induced cardiotoxicity.
| Study ID | Animal model | Doxorubicin dose and route | MSCs type and source | MSCs dose | Route and time of MSC administration | Findings |
|---|---|---|---|---|---|---|
| Chen et al. (2006) | Rabbit | 2 mg/kg per week for 8 weeks (i.p.) | BMMSCs or skeletal myoblasts (autologous) | 1 × 107 | Intracoronary, 4 weeks after Dox treatment | The LVEF was not significantly improved in either the BMMSCs or skeletal myoblast-treated groups. |
| Garbade et al. (2009) | Rabbit | 3 mg/kg for 6 weeks (i.p.) | BMMSCs (autologous) | 1.5/2 × 106 | Epimyocardial, 2 weeks after Dox treatment | BMMSCs treatment significantly increased the LVEF. On histological examination, cell-treated hearts exhibited less collagen content and higher capillary density. However, the transplanted cells did not show any cardiac markers. |
| Mohammadi Gorji et al. (2012) | Rat | Three doses of 2.5 mg/kg per week for 2 weeks (i.p.) | BMMSCs (heterologous) | 5 × 106 | Intravenous, 2 weeks after Dox treatment | Both MSCs and its conditioned medium significantly reduced myocardial fibrosis and Bcl-2 expression. Compared to the standard medium, the MSC-conditioned medium had significantly higher levels of HGF and IGF. |
| Yu et al. (2014) | Rat | 2.5 mg/kg per week for 6 weeks (i.p.) | BMMSCs (heterologous) | 5 × 106 | Intravenous, one injection per day (10 times)/10 weeks after Dox treatment | The survival rate and LVEF in rats treated with MSCs, compared to placebo-treated rats. Further, MSC treatment reduced myocardial collagen volume fraction and mRNA expression of TGF-β1, AT1, and CYP11B2. |
| Ammar et al. (2015) | Rat (diabetic) | 2.5 mg/kg 3 times/week for 2 weeks (i.p.) | BMMSCs and ADSCs (from human tissues) | 2 × 106 for either cell type | Intravenous, 4 weeks after the last DOX injection | BM-MSCs and ADSCs were equally effective in alleviating DOX-induced cardiac damage by decreasing immune cell infiltration and collagen deposition and enhancing angiogenesis |
| Dias et al. (2015) | Rat | 3.75 mg/kg/day once a week for 4 weeks (i.p.) | BMMSCs and skeletal myoblasts (autologous) | 5 × 104 | Subepicardial, 4 weeks after the last dose of DOX | The combined stem cell treatment significantly improved the LVEF, compared to the saline-treated group. Histological examination showed proliferation of skeletal muscle cells in the myocardium. |
| Zhang et al. (2015) | Mouse | 3 mg/kg, 3 times per week for 2 weeks (i.p.) | Conditioned medium from BMMSCs (BMMSCs-CdM) or iPSC-derived MSCs | 50 μl of MSCs-CdM | Intramyocardial, after creation of the DOX-induced cardiomyopathy model | Compared to BM-MSCs-CdM, iPSC-MSCs-CdM treatment exhibited better alleviation of heart failure, as well as less cardiomyocyte apoptosis and fibrosis. |
| Deng et al. (2017) | Rat | 2.5 mg/kg for 2 weeks (i.p.) | BMMSCs (cells with or without Nkx2.5 transfection) | 1 × 107 | Intravenous, 3 weeks after Dox treatment | The LVEF was increased by 43.4% and 49.9% in rats treated with BMMSCs and Nkx2.5-transfected BMMSCs, respectively. Further, Nkx2.5 transfection improved MSCs differentiation into cardiomyocyte-like cells and reduced myocardial fibrosis. |
| Zeng et al. (2017) | Rat | 2 mg/kg seven times in 2 days (i.p.) | BMMSCs (heterologous) with and without miR-21 over expression | i.p., injection after cardiotoxicity induction | BMMSCs, overexpressing miR-21, exhibited more proliferation than untransfected cells and significantly enhanced expression of Bcl-2, VEGF and Cx43 and reduced expression of Bax, BNP and troponin T | |
| Soliman et al. (2017) | Rat | 450 mg/m2 for 3 consecutive days (i.p.) | BMMSCs (heterologous) with and without sodium valproate and electric stimulation (ES) over the shoulder | 5 × 105 | Intravenous, after DOX cardiotoxicity induction | Rats treated by BMMSCs and valproate/ES combination showed similar biochemical parameters to the control group, as well as better histopathological appearance and cardiac homing of MSCs than rats treated by stem cells alone. |
| Oliveira et al. (2013) | Rat | 5 mg/kg weekly for 4 weeks (i.p.) | ADSCs (heterologous) | 3 × 106 | Intravenous, prior to the beginning of the experiment | Unlike C. sinensis extract, treatment by ADSCs significantly improved the LVEF. However, no cell engraftment was detected in the host cardiac tissue. |
| Pınarlı et al. (2013) | Rat | 12 mg/kg as a single dose (i.p.) | ADSCs (alone or with resveratrol) | 2 × 106 | i.p., starting the day after DOX injection, then two times at 5 days interval | The best hemodynamic (left ventricular end diastolic pressure and the rate of pressure development, yet not significant) and histological outcomes were observed in the group, treated by resveratrol and ADSCs. |
| Gopinath et al. (2010) | Mouse and cultured neonatal rat cardiomyocytes | 400 ng/kg per minute (oral) | hUCB-MSCs (human placenta) | 2.5 × 106 | Intravenous, 2 weeks after Dox treatment | hUCB-MSCs exhibited differentiation into cardiomyocyte-like cells, reversed the pathological effects of DOX on cultured myocytes, and induced a shift from pathological hypertrophy towards physiological hypertrophy |
| Di et al. (2012) | Mouse | Three cycles of 3 doses of 2 mg/kg per week (i.p.) | hUCB-MSCs (human placenta) | 1 × 106 | Intravenous, at the end of each Dox cycle | MSC treatment significantly reduced myocardial necrosis and increased LVEF and fractional shortening, probably through reduction of oxidative stress. Further, MSCs treatment had no effect on tumor growth. |
| Mousa et al. (2018) | Rat | 1.25 mg/kg every other day for 1 month (i.p.) | hUCB-MSCs (human placenta) with carvedilol | 1.5 × 106 | Intravenous, single dose, along with carvedilol administration | The combination of hUCB and carvedilol reduced DOX-induced electrocardiographic abnormalities and cardiac concentrations of oxidative stress markers and caspase-3, while increased cardiac concentrations of VEGF and IGF-1 |
| Abd Allah and Hussein (2017) | Rat | 2.5 mg/kg every other day for 2 weeks (i.p.) | hUCB-MSCs (human placenta) | 5 × 106 | Intravenous, 1 week after the last DOX dose | Treatment by hUCB-MSCs resulted in significant amelioration of DOX-induced oxidative stress, ECG abnormalities and histopathological alterations. |
| Mao et al. (2017) | Rat | 2 mg/kg once a week for 8 weeks (i.p.) | hUCB-MSCs (human placenta) | 2.5 × 1 05 (low dose group) and 1 × 106 (high dose group) | Intramuscular, 2 weeks after the last DOX injection | Treatment by hUCB-MSCs significantly increased LVEF, as well as the expression of VEGF, IGF-1, and HGF in the myocardium and attenuated mitochondrial swelling and maintained sarcolemma integrity |
| Haydardedeoglu et al. (2018) | Rat | 2.5 mg/kg on day 1 and 4 mg/kg on day 21 | Fetal-derived MSCs | 2 × 106 | i.p., on days 7, 14, and 21 after the last DOX injection | The intraperitoneal route can be a valid alternative to the intravenous and intra-cardiac routes. |
ADSCs, adipose-derived stem cells; AT-1, angiotensin 1 receptor; BMMSCs, bone-marrow derived mesenchymal stem cells; BNP, brain naturetic peptide; hUCB, human umbilical cord blood; IGF, insulin-like growth factor; LVEF, left-ventricular ejection fraction; TGF-β1, transforming growth factor-β; VEGF, vascular endothelial growth factor.