Intramuscular injection of human umbilical cord-derived mesenchymal stem cells improves cardiac function in dilated cardiomyopathy rats

Abstract

BackgroundStem cells provide a promising candidate for the treatment of the fatal pediatric dilated cardiomyopathy (DCM). This study aimed to investigate the effects of intramuscular injection of human umbilical cord-derived mesenchymal stem cells (hUCMSCs) on the cardiac function of a DCM rat model.MethodsA DCM model was established by intraperitoneal injections of doxorubicin in Sprague-Dawley rats. hUCMSCs at different concentrations or cultured medium were injected via limb skeletal muscles, with blank medium injected as the control. The rats were monitored for 4 weeks, meanwhile BNP, cTNI, VEGF, HGF, GM-CSF, and LIF in the peripheral blood were examined by ELISA, and cardiac function was monitored by echocardiography (Echo-CG). Finally, the expression of IGF-1, HGF, and VEGF in the myocardium was examined by histoimmunochemistry and real-time PCR, and the ultrastructure of the myocardium was examined by electron microscopy.ResultsInjection of hUCMSCs markedly improved cardiac function in the DCM rats by significantly elevating left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS). The BNP and cTNI levels in the peripheral blood were reduced by hUCMSCs, while HGF, LIF, GM-CSF, and VEGF were increased by hUCMSCs. Expression of IGF-1, HGF, and VEGF in the myocardium from the DCM rats was significantly increased by hUCMSC injection. Furthermore, hUCMSCs protected the ultrastructure of cardiomyocytes by attenuating mitochondrial swelling and maintaining sarcolemma integrity.ConclusionsIntramuscular injection of UCMSCs can improve DCM-induced cardiac function impairment and protect the myocardium. These effects may be mediated by regulation of relevant cytokines in serum and the myocardium.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0472-y) contains supplementary material, which is available to authorized users.

Concise Review: Skeletal Muscle as a Delivery Route for Mesenchymal Stromal Cells

“…When hMSCs are IMtransplanted in immunocompetent animals, a short dwell time of 4-8 days has been reported by Prather et al [22], Francki et al [23], and Hamidian Jahromi et al [38]. Exceptions are the studies by Mao et al [36] and Shabbir et al [34] who reported therapeutic effects for 4 weeks that may infer survival of IM-transplanted hWJ-MSC or pBMMSCs in immunocompetent SD-rats and TO2 hamsters respectively, although more probably reflect the "hit-and-run" mechanism by which MSCs are considered to have their effects [55]. On the contrary, some of the studies that have IM-transplanted MSCs in genetically immunocompromised animal models have reported significant dwell times of 3-24 weeks in injured muscle [22,24,56], 4-16 weeks in intact skeletal muscle of animals with systemic disease [37,39], and 4-32 weeks in intact healthy animals [5,33,[57][58][59].…”

“…Similarly, Mao et al IM‐delivered human umbilical cord Wharton's jelly MSCs (hWJMSCs) into both fore limb and hind limbs of doxorubicin‐induced SD rats (a model of dilated cardiomyopathy), two injections 2 weeks apart. Improved cardiac function with increased systemic levels of HGF, IGF‐1, LIF, GM‐CSF, and VEGF and cardiac tissue expression level of HGF, VEGF, and IGF‐1 was observed 2 weeks after the second MSC injection . Furthermore, Liu et al, using human soluble tumor necrosis factor receptor (hsTNFR) transduced hBMMSCs demonstrated a prophylactic reduction in joint inflammation in an antibody‐induced/LPS‐challenged murine rheumatoid arthritis (RA) model, although the naïve hBMMSCs showed no effect .…”

“…On the contrary, Kang et al delivered high and low doses of hBMMSCs in ischemic limbs of Balb/c mice and reported no dose–effect relationship but enhanced results were obtained with higher frequency of MSC injection. Similarly, Mao et al injected hUCMSCs twice into both fore and hind limb musculature of DCM rats (see above), 2 weeks apart, but reported no differences in outcome with low and high dose (0.25 or 1 × 10 6 cells) although the second treatment did result in significant increase in left ventricular ejection fraction . On the other hand, Shabbir et al reported that the highest injection dose used, of 0.25, 1, and 4 × 10 6 pBMMSCs into bilateral hamstrings, resulted in the most effective cardiac function improvement in the recipient hamsters .…”

Wearable and Implantable Devices for Cardiovascular Healthcare: from Monitoring to Therapy Based on Flexible and Stretchable Electronics

“…In addition, the administration of autologous cardiosphere‐derived cells and human mesenchymal stem cells to an infarcted heart has shown therapeutic efficacy . These cells have been administered to subjects via intracoronary infusion and intramyocardial injection …”

Effects of exosomes from human umbilical cord mesenchymal stem cell on cardiac function in rats with dilated cardiomyopathy induced by Adriamycin

“…However, with the development of stem cell research, the low transplanting rate, tumorigenicity and the ethics of stem cell transplantation have been widely discussed.Our previous studies found that intramuscular injection of hucMSCs improved the cardiac function in Adriamycin-induced DCM rats, while the transplanted hucMSCs were mainly retained in the muscles,meanwhile the levels of HGF,IGF-1,LIF,GM-CSF and VEGF increased in the myocardium and circulation. The results suggested that paracrine mechanisms may contribute to the therapeutic effect of hucMSCs on DCM [4]. Fang et al found that hucMSC-Ex can reduce the scar formation in wound healing by inhibiting the TGF-b1/SAMD2 pathway [5].Other studies have demonstrated that both MSC and MSC-Ex can reduce the SCI-induced A1 astrocytes by inhibiting the nuclear transport of NF Bp65, thus playing an anti-in ammatory and neuroprotective role [6], but the speci c mechanism remains unknown.…”