Dickkopf Homolog 3 Induces Stem Cell Differentiation into Smooth Muscle Lineage Via ATF6 Signalling

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2015 Jun 25

PMID 26105053

Citations 25

Authors

Xiaocong Wang

Eirini Karamariti

Russell Simpson

Wen Wang

Qingbo Xu

Affiliations

Soon will be listed here.

Abstract

Smooth muscle cells (SMCs) are a key component of healthy and tissue engineered vessels and play a crucial role in vascular development and the pathogenic events of vascular remodeling i.e. restenosis. However, the cell source from which they can be isolated is limited. Embryonic stem (ES) cells that have the remarkable capability to differentiate into vascular SMCs in response to specific stimuli provide a useful model for studying SMC differentiation. Previous studies suggested that dickkopf homolog 3 (DKK3) has a role in human partially induced pluripotent stem cell to SMC differentiation. Here, we demonstrate that the expression of DKK3 is essential for the expression of SMC markers and myocardin at both the mRNA and protein levels during mouse ES cell differentiation into SMCs (ESC-SMC differentiation). Overexpression of DKK3 leads to further up-regulation of the aforementioned markers. Further investigation indicates that DKK3 added as a cytokine activates activating transcription factor 6 (ATF6), leading to the increased binding of ATF6 on the myocardin promoter and increased its expression. In addition, inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) promotes the expression of ATF6 and leads to further increase of myocardin transcription. Our findings offer a novel mechanism by which DKK3 regulates ESC-SMC differentiation by activating ATF6 and promoting myocardin expression.

Citing Articles

A myofiber-derived secreted factor for muscle regeneration.

Xiao F, Sun Z Life Metab. 2025; 2(4):load025.

PMID: 39872244 PMC: 11749707. DOI: 10.1093/lifemeta/load025.

The tunicamycin derivative TunR2 exhibits potent antibiotic properties with low toxicity in an in vivo Mycobacterium marinum-zebrafish TB infection model.

Nonarath H, Jackson M, Penoske R, Zahrt T, Price N, Link B J Antibiot (Tokyo). 2024; 77(4):245-256.

PMID: 38238588 PMC: 11403873. DOI: 10.1038/s41429-023-00694-z.

The Multifaceted Role of Human Dickkopf-3 (DKK-3) in Development, Immune Modulation and Cancer.

Mourtada J, Thibaudeau C, Wasylyk B, Jung A Cells. 2024; 13(1).

PMID: 38201279 PMC: 10778571. DOI: 10.3390/cells13010075.

Myofiber Baf60c controls muscle regeneration by modulating Dkk3-mediated paracrine signaling.

Xu J, Li X, Chen W, Zhang Z, Zhou Y, Gou Y J Exp Med. 2023; 220(9).

PMID: 37284884 PMC: 10250555. DOI: 10.1084/jem.20221123.

Dickkopf-3: An Update on a Potential Regulator of the Tumor Microenvironment.

Al Shareef Z, Ershaid M, Mudhafar R, Soliman S, Kypta R Cancers (Basel). 2022; 14(23).

PMID: 36497305 PMC: 9738550. DOI: 10.3390/cancers14235822.

References

Gittenberger-de Groot A, DeRuiter M, Bergwerff M, Poelmann R . Smooth muscle cell origin and its relation to heterogeneity in development and disease. Arterioscler Thromb Vasc Biol. 1999; 19(7):1589-94. DOI: 10.1161/01.atv.19.7.1589. View

Owens G . Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 1995; 75(3):487-517. DOI: 10.1152/physrev.1995.75.3.487. View

Xu C, Bailly-Maitre B, Reed J . Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest. 2005; 115(10):2656-64. PMC: 1236697. DOI: 10.1172/JCI26373. View

Xiao Q, Zeng L, Zhang Z, Hu Y, Xu Q . Stem cell-derived Sca-1+ progenitors differentiate into smooth muscle cells, which is mediated by collagen IV-integrin alpha1/beta1/alphav and PDGF receptor pathways. Am J Physiol Cell Physiol. 2006; 292(1):C342-52. DOI: 10.1152/ajpcell.00341.2006. View

Rudijanto A . The role of vascular smooth muscle cells on the pathogenesis of atherosclerosis. Acta Med Indones. 2007; 39(2):86-93. View

Xie C, Zhang J, Villacorta L, Cui T, Huang H, Chen Y . A highly efficient method to differentiate smooth muscle cells from human embryonic stem cells. Arterioscler Thromb Vasc Biol. 2007; 27(12):e311-2. DOI: 10.1161/ATVBAHA.107.154260. View

Huang J, Cheng L, Li J, Chen M, Zhou D, Lu M . Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice. J Clin Invest. 2008; 118(2):515-25. PMC: 2176191. DOI: 10.1172/JCI33304. View

Lee E, Jo M, Rho S, Park K, Yoo Y, Park J . Dkk3, downregulated in cervical cancer, functions as a negative regulator of beta-catenin. Int J Cancer. 2008; 124(2):287-97. DOI: 10.1002/ijc.23913. View

Margariti A, Xiao Q, Zampetaki A, Zhang Z, Li H, Martin D . Splicing of HDAC7 modulates the SRF-myocardin complex during stem-cell differentiation towards smooth muscle cells. J Cell Sci. 2009; 122(Pt 4):460-70. DOI: 10.1242/jcs.034850. View

10.

Watanabe M, Kashiwakura Y, Huang P, Ochiai K, Futami J, Li S . Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression. Int J Oncol. 2009; 34(3):657-63. DOI: 10.3892/ijo_00000191. View

11.

Xiao Q, Luo Z, Pepe A, Margariti A, Zeng L, Xu Q . Embryonic stem cell differentiation into smooth muscle cells is mediated by Nox4-produced H2O2. Am J Physiol Cell Physiol. 2008; 296(4):C711-23. DOI: 10.1152/ajpcell.00442.2008. View

12.

Pepe A, Xiao Q, Zampetaki A, Zhang Z, Kobayashi A, Hu Y . Crucial role of nrf3 in smooth muscle cell differentiation from stem cells. Circ Res. 2010; 106(5):870-9. DOI: 10.1161/CIRCRESAHA.109.211417. View

13.

Margariti A, Zampetaki A, Xiao Q, Zhou B, Karamariti E, Martin D . Histone deacetylase 7 controls endothelial cell growth through modulation of beta-catenin. Circ Res. 2010; 106(7):1202-11. DOI: 10.1161/CIRCRESAHA.109.213165. View

14.

Chiu C, Wang B, Chung T, Shyu K . Angiotensin II and the ERK pathway mediate the induction of myocardin by hypoxia in cultured rat neonatal cardiomyocytes. Clin Sci (Lond). 2010; 119(7):273-82. PMC: 2890999. DOI: 10.1042/CS20100084. View

15.

Nakamura R, Hackam A . Analysis of Dickkopf3 interactions with Wnt signaling receptors. Growth Factors. 2010; 28(4):232-42. PMC: 2950226. DOI: 10.3109/08977191003738832. View

16.

Zhang L, Jin M, Margariti A, Wang G, Luo Z, Zampetaki A . Sp1-dependent activation of HDAC7 is required for platelet-derived growth factor-BB-induced smooth muscle cell differentiation from stem cells. J Biol Chem. 2010; 285(49):38463-72. PMC: 2992279. DOI: 10.1074/jbc.M110.153999. View

17.

Gu Y, Ma Y, Zhao W, Chen J . Dickkopf3 overexpression inhibits pancreatic cancer cell growth in vitro. World J Gastroenterol. 2011; 17(33):3810-7. PMC: 3181442. DOI: 10.3748/wjg.v17.i33.3810. View

18.

Veeck J, Dahl E . Targeting the Wnt pathway in cancer: the emerging role of Dickkopf-3. Biochim Biophys Acta. 2011; 1825(1):18-28. DOI: 10.1016/j.bbcan.2011.09.003. View

19.

Xiao Q, Pepe A, Wang G, Luo Z, Zhang L, Zeng L . Nrf3-Pla2g7 interaction plays an essential role in smooth muscle differentiation from stem cells. Arterioscler Thromb Vasc Biol. 2012; 32(3):730-44. DOI: 10.1161/ATVBAHA.111.243188. View

20.

Tang Z, Wang A, Yuan F, Yan Z, Liu B, Chu J . Differentiation of multipotent vascular stem cells contributes to vascular diseases. Nat Commun. 2012; 3:875. PMC: 3538044. DOI: 10.1038/ncomms1867. View