Abstract
Background: The vast majority of cells delivered into the heart by conventional means are lost within the first 24 hours. Cardiosphere-derived cells (CDCs) face the same fate, suggesting that novel methods are needed to enhance retention. Methods and Results: We tested a cell-hydrogel delivery strategy. CDCs were grown from adult human cardiac biopsy specimens (n=7). In situ polymerizable hydrogels made of hyaluronan and porcine gelatin (HyStem-C™, Glycosan Biosciences) were formulated as a liquid at room temperature so as to gel within 20 minutes at 37°C. We verified that such a formulation could be passed through human injection catheters with full cell product recovery and viability. In vitro , average CDC viability in HyStem-C assayed using WST-8 was 87±9% after 72 hrs in culture, and remained high after one week (84±19%). Trans-membrane migration assays showed the migration capacity of CDCs was not compromised in the HyStem-C. Myocardial infarction was created in SCID mice and CDCs were injected intramyocardially in the infarct border zone. 24 hours after injection, real time PCR revealed a small fraction (5.8±2.2%, n=4) of CDCs delivered in conventional vehicle (PBS) engrafted. In contrast, engraftment of CDCs delivered in HyStem-C was increased by nearly an order of magnitude (35.0±25.2%, n=5, p<0.05). The superior engraftment persisted for at least 3 weeks (n=3; 1.2±0.4% vs. 5.9±0.5%, p<0.05). Cardiac echos (n=7-8 per group), analyzed in a blinded manner, revealed comparable LVEFs two hours post-MI, indicating similar ischemic injury among groups. At 3 weeks, LVEF deteriorated in the control (PBS only) group (-9.4±4.4%). In contrast, HyStem-C alone or CDC alone preserved LVEF (+0.5±8.6% and +5.8±5.3%, respectively), while HyStem-C + CDC resulted in a sizable boost in LVEF (+16.6±4.3%). Three weeks after treatment, the highest cardiac function was seen in the HyStem-C + CDC group (p<0.05 vs others). Quantitative morphometry revealed the greatest attenuation of LV remodeling in the HyStem-C + CDC group, with smallest infarct size and thickest infarct walls (n=4; p<0.05). Conclusions: A CDC/hydrogel formulation suitable for catheter-based intramyocardial injection exhibits superior engraftment and functional benefits relative to naked CDCs.
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