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

[51] Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages [J].

Seaberg, RM ;

Smukler, SR ;

Kieffer, TJ ;

Enikolopov, G ;

Asghar, Z ;

Wheeler, MB ;

Korbutt, G ;

van der Kooy, D .

NATURE BIOTECHNOLOGY, 2004, 22 (09) :1115-1124

[52] The Adult Mouse and Human Pancreas Contain Rare Multipotent Stem Cells that Express Insulin [J].

Smukler, Simon R. ;

Arntfield, Margot E. ;

Razavi, Rozita ;

Bikopoulos, George ;

Karpowicz, Phillip ;

Seaberg, Raewyn ;

Dai, Feihan ;

Lee, Simon ;

Ahrens, Rosemary ;

Fraser, Paul E. ;

Wheeler, Michael B. ;

van der Kooy, Derek .

CELL STEM CELL, 2011, 8 (03) :281-293

[53] Self-renewal of embryonic-stem-cell-derived progenitors by organ-matched mesenchyme [J].

Sneddon, Julie B. ;

Borowiak, Malgorzata ;

Melton, Douglas A. .

NATURE, 2012, 491 (7426) :765-+

[54] Intestinal Crypt Homeostasis Results from Neutral Competition between Symmetrically Dividing Lgr5 Stem Cells [J].

Snippert, Hugo J. ;

van der Flier, Laurens G. ;

Sato, Toshiro ;

van Es, Johan H. ;

van den Born, Maaike ;

Kroon-Veenboer, Carla ;

Barker, Nick ;

Klein, Allon M. ;

van Rheenen, Jacco ;

Simons, Benjamin D. ;

Clevers, Hans .

CELL, 2010, 143 (01) :134-144

[55] Prominin-1/CD133 Marks Stem Cells and Early Progenitors in Mouse Small Intestine [J].

Snippert, Hugo J. ;

van Es, Johan H. ;

van den Born, Maaike ;

Begthel, Harry ;

Stange, Daniel E. ;

Barker, Nick ;

Clevers, Hans .

GASTROENTEROLOGY, 2009, 136 (07) :2187-2194

[56] Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice [J].

Soria, B ;

Roche, E ;

Berná, G ;

León-Quinto, T ;

Reig, JA ;

Martín, F .

DIABETES, 2000, 49 (02) :157-162

[57] Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles [J].

Subramanian, A ;

Tamayo, P ;

Mootha, VK ;

Mukherjee, S ;

Ebert, BL ;

Gillette, MA ;

Paulovich, A ;

Pomeroy, SL ;

Golub, TR ;

Lander, ES ;

Mesirov, JP .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (43) :15545-15550

[58] Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss [J].

Thorel, Fabrizio ;

Nepote, Virginie ;

Avril, Isabelle ;

Kohno, Kenji ;

Desgraz, Renaud ;

Chera, Simona ;

Herrera, Pedro L. .

NATURE, 2010, 464 (7292) :1149-1154

[59] Neurogenin 3+ cells contribute to β-cell neogenesis and proliferation in injured adult mouse pancreas [J].

Van de Casteele, M. ;

Leuckx, G. ;

Baeyens, L. ;

Cai, Y. ;

Yuchi, Y. ;

Coppens, V. ;

De Groef, S. ;

Eriksson, M. ;

Svensson, C. ;

Ahlgren, U. ;

Ahnfelt-Ronne, J. ;

Madsen, O. D. ;

Waisman, A. ;

Dor, Y. ;

Jensen, J. N. ;

Heimberg, H. .

CELL DEATH & DISEASE, 2013, 4 :e523-e523

[60] CHANGES IN THE MOUSE EXOCRINE PANCREAS AFTER PANCREATIC DUCT LIGATION - A QUALITATIVE AND QUANTITATIVE HISTOLOGICAL STUDY [J].

WATANABE, S ;

ABE, K ;

ANBO, Y ;

KATOH, H .

ARCHIVES OF HISTOLOGY AND CYTOLOGY, 1995, 58 (03) :365-374

← 1 2 3 4 5 6 7 →