Trop2 regulates the proliferation and differentiation of murine compact-bone derived MSCs

Yang,Jianye; Zhu,Zhaohui; Wang,Hongfei; Li,Feifei; Du,Xinling; Ma,Runlin  Z.

doi:10.3892/ijo.2013.1987

Trop2 regulates the proliferation and differentiation of murine compact-bone derived MSCs

Authors:
- Jianye Yang
- Zhaohui Zhu
- Hongfei Wang
- Feifei Li
- Xinling Du
- Runlin Z. Ma
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Affiliations: Department of Cardio-Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, State Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, P.R. China, Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
Published online on: June 19, 2013 https://doi.org/10.3892/ijo.2013.1987
Pages: 859-867

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Abstract

Mesenchymal stem cells (MSCs) show promising potential in cell-based therapies for wound repair and tissue engineering. However, their applications are hindered by our limited understanding of the detailed regulation of the cell fates in vitro and in vivo. To investigate the relationship between MSCs and Trop2, a protein overexpressed in cancer cells, we constructed a Trop2 gene knockout mouse by homologous recombination. Herein, we report that Trop2 is expressed exclusively on the MSC membrane and is involved in the regulation of proliferation and differentiation of MSCs. The proliferation of MSCs in Trop2 KO mice was significantly inhibited with prolonged cellular doubling time and reduced cell numbers entering the S phase. Trop2 deficiency impaired the differentiation of MSCs by significant reduction of adipogenesis and osteogenesis. AKT activation was impaired and cyclin D1 expression was downregulated in the Trop2-deficient MSCs, resulting in significant delay in cell cycle progression and inhibition of MSC self-renewal. Collectively, our findings help to establish a close functional link between Trop2 and MSCs, and to provide a tool for future investigation of Trop2 in other types of stem cells.

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1	Caplan AI: Mesenchymal stem cells. J Orthop Res. 9:641–650. 1991. View Article : Google Scholar : PubMed/NCBI
2	Friedenstein AJ, Gorskaja JF and Kulagina NN: Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol. 4:267–274. 1976.PubMed/NCBI
3	Pittenger MF, Mackay AM, Beck SC, et al: Multilineage potential of adult human mesenchymal stem cells. Science. 284:143–147. 1999. View Article : Google Scholar : PubMed/NCBI
4	Jiang Y, Jahagirdar BN, Reinhardt RL, et al: Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 418:41–49. 2002. View Article : Google Scholar : PubMed/NCBI
5	Lee OK, Kuo TK, Chen WM, Lee KD, Hsieh SL and Chen TH: Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood. 103:1669–1675. 2004. View Article : Google Scholar : PubMed/NCBI
6	Song H, Song BW, Cha MJ, Choi IG and Hwang KC: Modification of mesenchymal stem cells for cardiac regeneration. Expert Opin Biol Ther. 10:309–319. 2010. View Article : Google Scholar : PubMed/NCBI
7	Mizuno H: Adipose-derived stem cells for tissue repair and regeneration: ten years of research and a literature review. J Nippon Med Sch. 76:56–66. 2009.PubMed/NCBI
8	Bianco P, Robey PG and Simmons PJ: Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell. 2:313–319. 2008. View Article : Google Scholar : PubMed/NCBI
9	Fong D, Moser P, Krammel C, et al: High expression of TROP2 correlates with poor prognosis in pancreatic cancer. Br J Cancer. 99:1290–1295. 2008. View Article : Google Scholar : PubMed/NCBI
10	Fong D, Spizzo G, Gostner JM, et al: TROP2: a novel prognostic marker in squamous cell carcinoma of the oral cavity. Mod Pathol. 21:186–191. 2008.PubMed/NCBI
11	Muhlmann G, Spizzo G, Gostner J, et al: TROP2 expression as prognostic marker for gastric carcinoma. J Clin Pathol. 62:152–158. 2009. View Article : Google Scholar : PubMed/NCBI
12	Nakashima K, Shimada H, Ochiai T, et al: Serological identification of TROP2 by recombinant cDNA expression cloning using sera of patients with esophageal squamous cell carcinoma. Int J Cancer. 112:1029–1035. 2004. View Article : Google Scholar : PubMed/NCBI
13	Ohmachi T, Tanaka F, Mimori K, Inoue H, Yanaga K and Mori M: Clinical significance of TROP2 expression in colorectal cancer. Clin Cancer Res. 12:3057–3063. 2006. View Article : Google Scholar : PubMed/NCBI
14	Wang J, Day R, Dong Y, Weintraub SJ and Michel L: Identification of Trop-2 as an oncogene and an attractive therapeutic target in colon cancers. Mol Cancer Ther. 7:280–285. 2008. View Article : Google Scholar : PubMed/NCBI
15	Goldstein AS, Lawson DA, Cheng D, Sun W, Garraway IP and Witte ON: Trop2 identifies a subpopulation of murine and human prostate basal cells with stem cell characteristics. Proc Natl Acad Sci USA. 105:20882–20887. 2008. View Article : Google Scholar : PubMed/NCBI
16	Okabe M, Tsukahara Y, Tanaka M, et al: Potential hepatic stem cells reside in EpCAM⁺ cells of normal and injured mouse liver. Development. 136:1951–1960. 2009. View Article : Google Scholar : PubMed/NCBI
17	Hall B, Limaye A and Kulkarni AB: Overview: generation of gene knockout mice. Curr Protoc Cell Biol. Chapter 19(Unit 19.12): 19.12.1–17. 2009. View Article : Google Scholar
18	Zhu H, Guo ZK, Jiang XX, et al: A protocol for isolation and culture of mesenchymal stem cells from mouse compact bone. Nat Protoc. 5:550–560. 2010. View Article : Google Scholar : PubMed/NCBI
19	Sun S, Guo Z, Xiao X, et al: Isolation of mouse marrow mesenchymal progenitors by a novel and reliable method. Stem Cells. 21:527–535. 2003. View Article : Google Scholar : PubMed/NCBI
20	Guo Z, Li H, Li X, et al: In vitro characteristics and in vivo immunosuppressive activity of compact bone-derived murine mesenchymal progenitor cells. Stem Cells. 24:992–1000. 2006. View Article : Google Scholar : PubMed/NCBI
21	Maxson S, Lopez EA, Yoo D, Danilkovitch-Miagkova A and Leroux MA: Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Transl Med. 1:142–149. 2012. View Article : Google Scholar : PubMed/NCBI
22	Wu Y, Chen L, Scott PG and Tredget EE: Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 25:2648–2659. 2007. View Article : Google Scholar : PubMed/NCBI
23	Cubas R, Li M, Chen C and Yao Q: Trop2: a possible therapeutic target for late stage epithelial carcinomas. Biochim Biophys Acta. 1796:309–314. 2009.PubMed/NCBI
24	Yu FX, Sun HQ, Janmey PA and Yin HL: Identification of a polyphosphoinositide-binding sequence in an actin monomer-binding domain of gelsolin. J Biol Chem. 267:14616–14621. 1992.PubMed/NCBI
25	Linnenbach AJ, Seng BA, Wu S, et al: Retroposition in a family of carcinoma-associated antigen genes. Mol Cell Biol. 13:1507–1515. 1993.PubMed/NCBI
26	El Sewedy T, Fornaro M and Alberti S: Cloning of the murine TROP2 gene: conservation of a PIP2-binding sequence in the cytoplasmic domain of TROP-2. Int J Cancer. 75:324–330. 1998.PubMed/NCBI
27	Taniguchi CM, Tran TT, Kondo T, et al: Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN. Proc Natl Acad Sci USA. 103:12093–12097. 2006. View Article : Google Scholar : PubMed/NCBI
28	Wan X, Dennis AT, Obejero-Paz C, et al: Oxidative inactivation of the lipid phosphatase and tensin homolog on chromosome ten (PTEN) as a novel mechanism of acquired long QT syndrome. J Biol Chem. 286:2843–2852. 2011. View Article : Google Scholar : PubMed/NCBI
29	Datta SR, Dudek H, Tao X, et al: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 91:231–241. 1997. View Article : Google Scholar : PubMed/NCBI
30	Brunet A, Bonni A, Zigmond MJ, et al: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 96:857–868. 1999. View Article : Google Scholar : PubMed/NCBI
31	Song G, Ouyang G and Bao S: The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 9:59–71. 2005. View Article : Google Scholar : PubMed/NCBI
32	Re RN and Cook JL: Senescence, apoptosis, and stem cell biology: the rationale for an expanded view of intracrine action. Am J Physiol Heart Circ Physiol. 297:H893–H901. 2009. View Article : Google Scholar : PubMed/NCBI
33	Sethe S, Scutt A and Stolzing A: Aging of mesenchymal stem cells. Ageing Res Rev. 5:91–116. 2006. View Article : Google Scholar : PubMed/NCBI
34	Lindsley CW: The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation: a 2009 update. Curr Top Med Chem. 10:458–477. 2010. View Article : Google Scholar : PubMed/NCBI
35	Litvinov SV, Velders MP, Bakker HA, Fleuren GJ and Warnaar SO: Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. J Cell Biol. 125:437–446. 1994. View Article : Google Scholar : PubMed/NCBI
36	Maetzel D, Denzel S, Mack B, et al: Nuclear signalling by tumour-associated antigen EpCAM. Nat Cell Biol. 11:162–171. 2009. View Article : Google Scholar : PubMed/NCBI
37	Wang J, Zhang K, Grabowska D, et al: Loss of Trop2 promotes carcinogenesis and features of epithelial to mesenchymal transition in squamous cell carcinoma. Mol Cancer Res. 9:1686–1695. 2011. View Article : Google Scholar : PubMed/NCBI