Improved conduction and increased cell retention in healed MI using mesenchymal stem cells suspended in alginate hydrogel

Abstract

Introduction Mesenchymal stem cells (MSCs) have been associated with reduced arrhythmias; however, the mechanism of this action is unknown. In addition, limited retention and survival of MSCs can significantly reduce efficacy. We hypothesized that MSCs can improve impulse conduction and that alginate hydrogel will enhance retention of MSCs in a model of healed myocardial infarction (MI). Methods and results Four weeks after temporary occlusion of the left anterior descending artery (LAD), pigs (n=13) underwent a sternotomy to access the infarct and then were divided into two studies. In study 1, designed to investigate impulse conduction, animals were administered, by border zone injection, 9–15 million MSCs (n=7) or phosphate-buffered saline (PBS) (control MI, n=5). Electrogram width measured in the border zone 2 weeks after injections was significantly decreased with MSCs (−30±8 ms, p<0.008) but not in shams (4±10 ms, p=NS). Optical mapping from border zone tissue demonstrated that conduction velocity was higher in regions with MSCs (0.49±0.03 m/s) compared to regions without MSCs (0.39±0.03 m/s, p<0.03). In study 2, designed to investigate MSC retention, animals were administered an equal number of MSCs suspended in either alginate (2 or 1 % w/v) or PBS (n=6/group) by border zone injection. Greater MSC retention and survival were observed with 2 % alginate compared to PBS or 1 % alginate. Confocal immunofluorescence demonstrated that MSCs survive and are associated with expression of connexin-43 (Cx43) for either PBS (control), 1 %, or 2 % alginate. Conclusions For the first time, we are able to directly associate MSCs with improved impulse conduction and increased retention and survival using an alginate scaffold in a clinically relevant model of healed MI.

Mesenchymal stem cells suppress cardiac alternans by activation of PI3K mediated nitroso-redox pathway

“…Nevertheless, in those previous studies MSCs were co-cultured with normal cardiomyocytes, which may not be the actual clinical setting. For example, we have previously shown that when MSCs are infused at the time of injury arrhythmia vulnerability is decreased [49], and when MSCs are directly injected into borderzone tissue impulse conduction slowing is reduced [50]. Moreover, as suggested in the present study paracrine action may also lessen Ca ++ mediated arrhythmia substrates such as alternans, which are heightened in the infarct border zone [26, 51].…”

Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction

“…We have found that administration of c-kit POS cardiac progenitors cells (CPCs) results in a sustained (up to 1 year) improvement in left ventricular (LV) function and structure despite the fact that almost all exogenous cells disappear within a few days of transplantation [6, 7, 14, 15, 19, 28, 30, 31, 33]. Similar findings have been reported by others with various cell types [1–4, 8, 13, 16, 17, 23–25, 32, 36]. In view of the fact that transplanted cells are rapidly cleared from the myocardium, we posit that administration of one dose of cells cannot be regarded as a valid test of the therapeutic efficacy of that product.…”

Design of Injectable Materials to Improve Stem Cell Transplantation

“…Further studies have shown that the concentration of alginate, and thus mechanical stiffness, also plays a significant role in cell retention. MSCs transplanted in a 2% alginate solution (~2 kPa) were found to be retained and survive 4x higher than that of cells transplanted with saline or even 1% alginate (~700 Pa) [105]. …”