Enhancing retention and efficacy of cardiosphere-derived cells administered after myocardial infarction using a hyaluronan-gelatin hydrogel

Abstract

Cardiosphere-derived cells (CDCs) are under clinical development and are currently being tested in a clinical trial enrolling patients who have undergone a myocardial infarction. CDCs are presently administered via infusion into the infarct-related artery and have been shown in early clinical trials to be effective agents of myocardial regeneration. This review describes the administration of CDCs in a hyaluronan-gelatin hydrogel via myocardial injection and the subsequent improvements in therapeutic benefit seen in animal models. Development of a next generation therapy involving the combination of CDCs and hydrogel is discussed.

Keywords: ALLSTAR trial; CADUCEUS trial; cardiosphere-derived cells; hyaluronan-gelatin hydrogel; myocardial infarction.

Figure 1. CDC surface markers compatible with hydrogel. Representative flow cytometry histograms showing expression of CD49a (A), CD49b (B), CD49c (C) and CD44 (D) in CDCs (in blue). Isotype controls are shown in red.

Figure 2. CDC survival in the hydrogel. (A and B) Representative fluorescent micrographs showing live (Calcien-AM: green) and dead (EthD: red) staining of CDCs cultured in Hystem™ and Hystem-C^TM for 7 d. (C) CCK-8 assay quantifying cell survival rates in Hystem^TM (black bars) or Hystem-C^TM (green bars) (n = 3). * indicates p < 0.05 when compared with Hystem^TM.

Figure 3. Enhanced cell engraftment by delivering CDCs in Hystem-C^TM. (A and B) Representative confocal images showing engraftment of DiI-labeled human CDCs (red) 24 h after injection into post-MI mouse hearts. (C) Quantitative PCR analysis of cell engraftment rates in the mouse hearts 3 weeks post injection (n = 3). * indicates p < 0.05 when compared with “CDC in PBS.”

Figure 4. Cardiac function and heart morphometry. (A) Changes of left ventricular ejection fraction (LVEF) measured by echocardiography from baseline to 3 weeks in each group. (B) Quantitative analysis and LV morphometric parameters of Masson’s trichrome images (n = 3–5 mice per group). * indicates p < 0.05 when compared with Control. ** indicates p < 0.05 when compared with any other group.

Figure 5. Promotion of angiogenesis by CDC/hydrogel transplantation. (A) Representative confocal images showing α smooth muscle actin-positive vasculature in the hearts receiving various treatment products. (B) Quantitation of α smooth muscle actin-positive vasculature in various groups (n = 5 mice per group). * indicates p < 0.05 when compared with Control. ** indicates p < 0.05 when compared with any other group. Bar = 200 µm.