Abstract 15675: Bone Marrow Derived Ixmyelocel-T From Patients With Severe Ischemic Dilated Cardiomyopathy Display Robust Anti-Inflammatory and Pro-Angiogenic Properties
| Autor: | Kelly J Ledford, Ann E Remmers, Ross Tubo |
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| Rok vydání: | 2014 |
| Předmět: | |
| Zdroj: | Circulation. 130 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circ.130.suppl_2.15675 |
| Popis: | Ixmyelocel-T, an expanded autologous multicellular therapy cultured from BMMNCs consisting of regenerative MSCs and M2-like macrophages, has shown clinical promise in the treatment of ischemic DCM. However the quality of BM-derived cell therapies from patients with severe heart failure is unclear as reports suggest they are dysfunctional due to advanced age and the systemic disease state. We hypothesized that ixmyelocel-T generated from ischemic DCM patients BMMNCs would consist of expanded MSCs and M2 macrophages, and produce anti-inflammatory and angiogenic factors useful for cardiac repair. BMMNCs were obtained from 55-80 year old ischemic DCM patients, with LVEF < 35% and NYHA Class III or IV, enrolled in the phase 2b clinical IXCELL-DCM trial. The BMMNCs were either used in experiments or expanded in a closed bioreactor system for 12 days to generate ixmyelocel-T (n = 13). FACS revealed a 50 ± 5% fold expansion in CD90+ MSC and a 96 ± 39% fold expansion in CD14+ M2-like macrophages in ixmyelocel-T. Cytokine arrays revealed ixmyelocel-T secreted more regulatory and trophic factors compared to BMMNCs. Specifically, ixmyelocel-T secreted significantly more Flt-3L, GM-CSF, IL-10, IL-13, IL-1ra, IL-2, IL-3, IL-5, MCP-1, CCL18, TGF-β, angiopoietin-2, IL-8, TIMP-1, TIMP-2, and VEGF compared to BMMNCs. ELISA analysis confirmed that ixmyelocel-T secreted significantly higher levels of IL-10 (2092 ± 183 vs 130 ± 17 pg/mL, p < 0.001) and IL-1ra (12241 ± 2806 vs 1857 ± 564, p < 0.001) after LPS challenge. Ixmyelocel-T had higher gene expression of the anti-inflammatory and pro-angiogenic markers HMOX1, CCL18, FGF2, IGF1, PGF, SDF-1α, Ang-1, Ang-2 and lower levels of the pro-inflammatory markers TNFα, IL-1β, IFN[[Unable to Display Character: ɣ]], IL-12 compared to BMMNCs after LPS challenge. Additionally, co-culture of ixmyelocel-T with HUVECs resulted in significant wound healing in an in vitro scratch assay compared to BMMNCs (56 ± 4 vs 39 ± 8%, p < 0.001). This data suggests that the process used to generate ixmyelocel-T is ideal for the therapeutic expansion of BMMNCs from patients with severe cardiac diseases. Ixmyelocel-T retains a regenerative, anti-inflammatory, and pro-angiogenic profile which holds promise for treatment in advanced cardiac diseases where treatment options are limited. |
| Databáze: | OpenAIRE |
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