Research ArticleStem Cell Biology

Autocrine Wnt regulates the survival and genomic stability of embryonic stem cells

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Sci. Signal.  10 Jan 2017:
Vol. 10, Issue 461, eaah6829
DOI: 10.1126/scisignal.aah6829

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Genomic instability without Wnt

Unlike most cells in the body, embryonic stem cells renew themselves and can differentiate into almost any cell type. Although embryonic stem cells have been proposed to treat a myriad of human diseases, their use is fraught with the risk of the formation of noncancerous tumors called teratomas. The Wnt family of ligands promotes both the self-renewal and differentiation of embryonic stem cells. Augustin et al. either genetically ablated or overexpressed Evi, a protein that transports Wnts through the secretory pathway, in mouse embryonic stem cells, which would be expected to block or enhance the secretion of any of the Wnt family of ligands produced by these cells. Reducing Wnt secretion reduced the incidence of teratoma formation by Evi-deficient embryonic stem cells injected into mice. Furthermore, Wnt secretion ensured that proliferating embryonic stem cells segregated chromosomes properly and did not undergo apoptosis. Thus, enhancing Wnt signaling may prevent genomic instability in embryonic stem cells, which could help advance therapeutic application of stem cells.

Abstract

Wnt signaling plays an important role in the self-renewal and differentiation of stem cells. The secretion of Wnt ligands requires Evi (also known as Wls). Genetically ablating Evi provides an experimental approach to studying the consequence of depleting all redundant Wnt proteins, and overexpressing Evi enables a nonspecific means of increasing Wnt signaling. We generated Evi-deficient and Evi-overexpressing mouse embryonic stem cells (ESCs) to analyze the role of autocrine Wnt production in self-renewal and differentiation. Self-renewal was reduced in Evi-deficient ESCs and increased in Evi-overexpressing ESCs in the absence of leukemia inhibitory factor, which supports the self-renewal of ESCs. The differentiation of ESCs into cardiomyocytes was enhanced when Evi was overexpressed and teratoma formation and growth of Evi-deficient ESCs in vivo were impaired, indicating that autocrine Wnt ligands were necessary for ESC differentiation and survival. ESCs lacking autocrine Wnt signaling had mitotic defects and showed genomic instability. Together, our study demonstrates that autocrine Wnt secretion is important for the survival, chromosomal stability, differentiation, and tumorigenic potential of ESCs.

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