Aldehyde Dehydrogenases: Not Just Markers, but Functional Regulators of Stem Cells

Giuseppe Vassalli, Giuseppe Vassalli

Abstract

Aldehyde dehydrogenase (ALDH) is a superfamily of enzymes that detoxify a variety of endogenous and exogenous aldehydes and are required for the biosynthesis of retinoic acid (RA) and other molecular regulators of cellular function. Over the past decade, high ALDH activity has been increasingly used as a selectable marker for normal cell populations enriched in stem and progenitor cells, as well as for cell populations from cancer tissues enriched in tumor-initiating stem-like cells. Mounting evidence suggests that ALDH not only may be used as a marker for stem cells but also may well regulate cellular functions related to self-renewal, expansion, differentiation, and resistance to drugs and radiation. ALDH exerts its functional actions partly through RA biosynthesis, as all-trans RA reverses the functional effects of pharmacological inhibition or genetic suppression of ALDH activity in many cell types in vitro. There is substantial evidence to suggest that the role of ALDH as a stem cell marker comes down to the specific isoform(s) expressed in a particular tissue. Much emphasis has been placed on the ALDH1A1 and ALDH1A3 members of the ALDH1 family of cytosolic enzymes required for RA biosynthesis. ALDH1A1 and ALDH1A3 regulate cellular function in both normal stem cells and tumor-initiating stem-like cells, promoting tumor growth and resistance to drugs and radiation. An improved understanding of the molecular mechanisms by which ALDH regulates cellular function will likely open new avenues in many fields, especially in tissue regeneration and oncology.

Figures

Figure 1
Figure 1
Flow cytometry analysis of ALDH activity in cells isolated from a human cardiac atrial appendage tissue specimen using the Aldefluor™ assay. (a) ALDHbr gating is established by incubating Aldefluor™-reacted cells with the ALDH inhibitor DEAB (negative control). An ALDH/side scatter (SSC) plot is shown. ALDHbr gating was set to include the top 0.05% of DEAB-treated cells with respect to the intensity of the fluorescent signal. (b) Aldefluor-reacted cells analyzed in the absence of DEAB treatment.
Figure 2
Figure 2
Model of ALDH1A1 regulation, potential retinoid signaling pathways, and functional effects of ALDH in CSCs. Retinol is oxidized to retinal by retinol dehydrogenases, and retinal is then oxidized to RA by ALDH1 enzymes (green dotted line). In the classic pathway, RA enters the nucleus and binds to dimers of RARα and RXRs triggering the expression of its downstream target genes including RARβ (yellow dotted line). In the nonclassic pathway, RA binds to dimers of RXRs and PPARβ/δ to induce the expression of its downstream target genes including Akt (orange dotted line). In cells expressing ERα, RA can bind to dimers of RXRs and ERα (not shown). RA can also bind with RARα outside the nucleus to activate the PI3K/Akt pathway. Wnt pathway regulates ALDH1A1 through β-catenin/TCF-dependent transcription. MUC1-C induces ERK signaling and phosphorylates C/EBPβ. The complex of MUC1-C and C/EBPβ occupies the sequence upstream from the transcription initiation site of ALDH1, triggering ALDH1A1 expression. TGF-β-induced Smad4 downregulates ALDH1 (red dotted line). Notch promotes ALDH activity in CSCs through induction of deacetylase SIRT2, leading to ALDH1A1 deacetylation, while ALDH1A1 acetylation by acetyltransferase PCAF inhibits ALDH activity (blue dotted line; some parts of this figure were adapted with modifications from Figures 1 and 2 from Xu et al. [20], with editor's permission).

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