Hyaluronan Enhances Bone Marrow Cell Therapy for Myocardial Repair After Infarction

Abstract

Hyaluronan (HA) has been shown to play an important role during early heart development and promote angiogenesis under various physiological and pathological conditions. In recent years, stem cell therapy, which may reduce cardiomyocyte apoptosis, increase neovascularization, and prevent cardiac fibrosis, has emerged as a promising approach to treat myocardial infarction (MI). However, effective delivery of stem cells for cardiac therapy remains a major challenge. In this study, we tested whether transplanting a combination of HA and allogeneic bone marrow mononuclear cells (MNCs) promotes cell therapy efficacy and thus improves cardiac performance after MI in rats. We showed that HA provided a favorable microenvironment for cell adhesion, proliferation, and vascular differentiation in MNC culture. Following MI in rats, compared with the injection of HA alone or MNC alone, injection of both HA and MNCs significantly reduced inflammatory cell infiltration, cardiomyocyte apoptosis, and infarct size and also improved cell retention, angiogenesis, and arteriogenesis, and thus the overall cardiac performance. Ultimately, HA/MNC treatment improved vasculature engraftment of transplanted cells in the infarcted region. Together, our results indicate that combining the biocompatible material HA with bone marrow stem cells exerts a therapeutic effect on heart repair and may further provide potential treatment for ischemic diseases.

Injection of autologous bone marrow cells in hyaluronan hydrogel improves cardiac performance after infarction in pigs

“…Therefore, cell retention was quantified by collecting periinfarct and infarct tissues from three cross-sections of the heart to estimate the total number. Interestingly, consistent with our previous finding in rats, we found that HA also facilitated the retention of MNCs at the injection site (4). Although the lifespan of HA may be short after injection, the retention rate of MNCs in the HA-MNC group showed an approximately twofold increase compared with that in the MNC-alone group, resulting in significant increases of angiogenesis and arteriogenesis in the HA-MNC group.…”

“…During the embryonic stage, HA is temporarily produced in the heart, and without HA, the formation of cardiac vasculature becomes abnormal (3). In a previous study (4), we demonstrated that HA enhances the therapeutic efficacy of bone marrow mononuclear cells (MNCs), which, in turn, reduces cardiomyocyte apoptosis and inflammatory cell infiltration at the early stage of MI. Furthermore, intramyocardial injection of HA-MNCs restores heart function by increasing cell retention, promoting neovascularization, and decreasing scar formation after MI in rats (4).…”

Towards the standardization of stem cell therapy studies for ischemic heart diseases: Bridging the gap between animal models and the clinical setting

“…After being administered, cells can be nearly gone as soon as 1 to 3 days after transplantation [44,45]. However, some authors reported signs of stem cell survival up to 1 week [8,16,60,100,104], 1 month [14,18,23,27,30,37,46,52,67,105] and, most strikingly, up to 1 year [26]. When retained cells are quantified, we find that less than 3% of the stem cells survive more than 4 weeks [59,70] and that percentage drops to levels below 1% when the assessment is made 16 weeks after transplantation [106].…”

“…Sustained release of stem cells using scaffolds, matrices or microcarriers The realization of the poor survival and retention of stem cells in the hostile myocardium has stimulated researchers to design strategies to protect them from the adversities found in an infarcted myocardium or in an already failing heart. Several hypotheses have been tested to shield cells from the hypoxic, serum-deprived, inflammatory, immuneactivated and pro-apoptotic infarcted/ischemic myocardium, namely the use of scaffolds, biomatrices, biomaterials, hydrogels (broadly accepted as synonyms) [17,18,20 [36]. Numerous biomaterials have been used to overcome this hurdle, such as hyaluronan, collagen I, agarose, fibrin, fibrinogen and alginate/chitosan combinations.…”

“…Also, they promote migration of endothelial cells and smooth muscle cells and, simultaneously, confer CMs protection from apoptosis. In addition, these materials have low immunogenicity and have anti-inflammatory and pro-angiogenic properties [17,18,20,37,50,53,67,107,108,112,115]. This explains why delivery of stem cells in scaffolds has higher benefits to those delivered in aqueous or in culture media, with regard to cell retention and proliferation as well as structural and functional myocardial recovery.…”