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Mechanisms of Action of Human Aldehyde Dehydrogenase Bright Cells in Therapy of Cardiovascular Diseases: Expression Analysis of Angiogenic Factors and Aldehyde Dehydrogenase Isozymes

Hannah Storrie White, Liisa Smith, Tracy Gentry and Andrew E. Balber

Human stem cell populations that express high aldehyde dehydrogenase activity [ALDHbr cells] have angiogenic activity in preclinical models and have been used safely to treat patients in early clinical trials. Bone marrow ALDHbr cells are being developed for therapeutic use in ischemic cardiovascular diseases. The mechanisms by which ALDHbr cells repair ischemic tissue are unknown, but available data suggest that angiogenic factors released by ALDHbr cells are involved. Gene expression studies were performed, and bone marrow ALDHbr cells were found to express 69 of 84 angiogenic factors tested. The 25 most highly expressed genes included soluble cytokines and growth factors, cytokine receptors, extracellular matrix proteins, and cell-cell signaling receptors. ALDHdim bone marrow cells that do not express high levels of ALDH and that have no angiogenic activity in preclinical models expressed a different group of genes. CD105 and Ephrin B4 transcripts were expressed about 65-fold more highly in ALDHbr than ALDHdim cells, and expression of these proteins was demonstrated in ALDHbr cells by flow cytometry. Expression analysis probing all 19 ALDH isozymes and immunofluorescence both demonstrated that ALDH1A1, an enzyme that can generate retinoic acids from retinaldehyde, was the ALDH isozyme most highly over expressed in ALDHbr cells compared to ALDHdim cells. Transwell studies demonstrated that ALDHbr cells responded to hypoxic conditions and to factors released from human endothelial vein cells (HUVEC) with changes in expression of specific angiogenic factors. Soluble factors released from ALDHbr cells in transwell cultures under hypoxic conditions stabilized endothelial tubules formed by HUVEC. The results are consistent with the hypothesis that human bone marrow ALDHbr cells can promote angiogenesis in ischemic tissues of patients with cardiovascular disease by several mechanisms including the release of soluble mediators.