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High aldehyde dehydrogenase (ALDH hi ) activity has been reported in normal and cancer stem cells. We and others have shown previously that human ALDH hi  cardiac atrial appendage cells are enriched with stem/progenitor cells. The role of ALDH in these cells is poorly understood but it may come down to the specific ALDH isoform(s) expressed. This study aimed to compare ALDH hi  and ALDH lo  atrial cells and to identify the isoform(s) that contribute to ALDH activity, and their functional role.   Methods and Results:  Cells were isolated from atrial appendage specimens from patients with ischemic and/or valvular heart disease undergoing heart surgery. ALDH hi  activity assessed with the Aldefluor reagent coincided with primitive surface marker expression (CD34 + ). Depending on their ALDH activity, RT-PCR analysis of ALDH hi  and ALDH lo  cells demonstrated a differential pattern of pluripotency genes (Oct 4, Nanog) and genes for more established cardiac lineages (Nkx2.5, Tbx5, Mef2c, GATA4). ALDH hi  cells, but not ALDH lo  cells, formed clones and were culture-expanded. When cultured under cardiac differentiation conditions, ALDH hi  cells gave rise to a higher number of cardiomyocytes compared with ALDH lo  cells. Among 19 ALDH isoforms known in human, ALDH1A3 was most highly expressed in ALDH hi  atrial cells. Knocking down ALDH1A3, but not ALDH1A1, ALDH1A2, ALDH2, ALDH4A1, or ALDH8A1 using siRNA decreased ALDH activity and cell proliferation in ALDH hi  cells. Conversely, overexpressing ALDH1A3 with a retroviral vector increased proliferation in ALDH lo  cells.   Conclusions:  ALDH1A3 is the key isoform responsible for ALDH activity in ALDH hi  atrial appendage cells, which have a propensity to differentiate into cardiomyocytes. ALDH1A3 affects  in vitro  proliferation of these cells.

frontiers in cardiovascular medicine

ALDH1A3 Is the Key Isoform That Contributes to Aldehyde Dehydrogenase Activity and Affects in Vitro Proliferation in Cardiac Atrial Appendage Progenitor Cells