Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis

被引：553

作者：

Huch, Meritxell ^{[1
]}

Bonfanti, Paola ^{[2
]}

Boj, Sylvia F. ^{[1
]}

Sato, Toshiro ^{[1
]}

Loomans, Cindy J. M. ^{[1
,3
]}

van de Wetering, Marc ^{[1
]}

Sojoodi, Mozhdeh ^{[2
]}

Li, Vivian S. W. ^{[1
]}

Schuijers, Jurian ^{[1
]}

Gracanin, Ana ^{[1
]}

Ringnalda, Femke ^{[1
,3
]}

Begthel, Harry ^{[1
]}

Hamer, Karien ^{[1
]}

Mulder, Joyce ^{[1
]}

van Es, Johan H. ^{[1
]}

de Koning, Eelco ^{[1
,3
]}

Vries, Robert G. J. ^{[1
]}

Heimberg, Harry ^{[2
]}

Clevers, Hans ^{[1
]}

机构：

[1] Univ Med Ctr Utrecht, Hubrecht Inst Dev Biol & Stem Cell Res, Utrecht, Netherlands

[2] Vrije Univ Brussel, Diabet Res Ctr, B-1090 Brussels, Belgium

[3] Leiden Univ, Med Ctr, Dept Nephrol, Leiden, Netherlands

来源：

EMBO JOURNAL | 2013年 / 32卷 / 20期

关键词：

EMBRYONIC STEM-CELLS; MOUSE PANCREAS; BETA-CELLS; ENDOCRINE-CELLS; SMALL-INTESTINE; ACINAR-CELLS; SELF-RENEWAL; LGR5; DIFFERENTIATION; REGENERATION;

D O I：

10.1038/emboj.2013.204

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Lgr5 marks adult stem cells in multiple adult organs and is a receptor for the Wnt-agonistic R-spondins (RSPOs). Intestinal, stomach and liver Lgr5(+) stem cells grow in 3D cultures to form ever-expanding organoids, which resemble the tissues of origin. Wnt signalling is inactive and Lgr5 is not expressed under physiological conditions in the adult pancreas. However, we now report that the Wnt pathway is robustly activated upon injury by partial duct ligation (PDL), concomitant with the appearance of Lgr5 expression in regenerating pancreatic ducts. In vitro, duct fragments from mouse pancreas initiate Lgr5 expression in RSPO1-based cultures, and develop into budding cyst-like structures (organoids) that expand five-fold weekly for >40 weeks. Single isolated duct cells can also be cultured into pancreatic organoids, containing Lgr5 stem/progenitor cells that can be clonally expanded. Clonal pancreas organoids can be induced to differentiate into duct as well as endocrine cells upon transplantation, thus proving their bi-potentiality.

引用

页码：2708 / 2721

页数：14

共 65 条

[1] Identification of stem cells in small intestine and colon by marker gene Lgr5 [J].

Barker, Nick ;

van Es, Johan H. ;

Kuipers, Jeroen ;

Kujala, Pekka ;

van den Born, Maaike ;

Cozijnsen, Miranda ;

Haegebarth, Andrea ;

Korving, Jeroen ;

Begthel, Harry ;

Peters, Peter J. ;

Clevers, Hans .

NATURE, 2007, 449 (7165) :1003-U1

[2] Lgr5+ve Stem Cells Drive Self-Renewal in the Stomach and Build Long-Lived Gastric Units In Vitro [J].

Barker, Nick ;

Huch, Meritxell ;

Kujala, Pekka ;

van de Wetering, Marc ;

Snippert, Hugo J. ;

van Es, Johan H. ;

Sato, Toshiro ;

Stange, Daniel E. ;

Begthel, Harry ;

van den Born, Maaike ;

Danenberg, Esther ;

van den Brink, Stieneke ;

Korving, Jeroen ;

Abo, Arie ;

Peters, Peter J. ;

Wright, Nick ;

Poulsom, Richard ;

Clevers, Hans .

CELL STEM CELL, 2010, 6 (01) :25-36

[3]

Bhushan A, 2001, DEVELOPMENT, V128, P5109

[4] Adult pancreatic acinar cells give rise to ducts but not endocrine cells in response to growth factor signaling [J].

Blaine, Stacy A. ;

Ray, Kevin C. ;

Anunobi, Reginald ;

Gannon, Maureen A. ;

Washington, Mary K. ;

Means, Anna L. .

DEVELOPMENT, 2010, 137 (14) :2289-2296

[5] The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia [J].

Blaydon, Diana C. ;

Ishii, Yoshiyuki ;

O'Toole, Edel A. ;

Unsworth, Harriet C. ;

Teh, Muy-Teck ;

Rueschendorf, Franz ;

Sinclair, Claire ;

Hopsu-Havu, Vaino K. ;

Tidman, Nicholas ;

Moss, Celia ;

Watson, Rosemarie ;

de Berker, David ;

Wajid, Muhammad ;

Christiano, Angela M. ;

Kelsell, David P. .

NATURE GENETICS, 2006, 38 (11) :1245-1247

[6] Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells [J].

Bonfanti, Paola ;

Claudinot, Stephanie ;

Amici, Alessandro W. ;

Farley, Alison ;

Blackburn, C. Clare ;

Barrandon, Yann .

NATURE, 2010, 466 (7309) :978-U105

[7] In vitro cultivation of human islets from expanded ductal tissue [J].

Bonner-Weir, S ;

Taneja, M ;

Weir, GC ;

Tatarkiewicz, K ;

Song, KH ;

Sharma, A ;

O'Neil, JJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (14) :7999-8004

[8]

Bouwens L, 1998, MICROSC RES TECHNIQ, V43, P332, DOI 10.1002/(SICI)1097-0029(19981115)43:4<332::AID-JEMT7>3.0.CO

[9]

2-1

[10] Multipotent Stem/Progenitor Cells in Human Biliary Tree Give Rise to Hepatocytes, Cholangiocytes, and Pancreatic Islets [J].

Cardinale, Vincenzo ;

Wang, Yunfang ;

Carpino, Guido ;

Cui, Cai-Bin ;

Gatto, Manuela ;

Rossi, Massimo ;

Berloco, Pasquale Bartolomeo ;

Cantafora, Alfredo ;

Wauthier, Eliane ;

Furth, Mark E. ;

Inverardi, Luca ;

Dominguez-Bendala, Juan ;

Ricordi, Camillo ;

Gerber, David ;

Gaudio, Eugenio ;

Alvaro, Domenico ;

Reid, Lola .

HEPATOLOGY, 2011, 54 (06) :2159-2172

← 1 2 3 4 5 6 7 →