Abstract 15675: Bone Marrow Derived Ixmyelocel-T From Patients With Severe Ischemic Dilated Cardiomyopathy Display Robust Anti-Inflammatory and Pro-Angiogenic Properties
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.
- Regenerative medicine stem cells
- Stem cell therapy
- Ischemic heart disease
- Older population
- Heart failure
Author Disclosures: K.J. Ledford: Employment; Significant; Employee of Aastrom Biosciences. A.E. Remmers: Employment; Significant; Employee of Aastrom Biosciences. R. Tubo: Employment; Significant; Employee of Aastrom Biosciences.
- © 2014 by American Heart Association, Inc.