Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals

Martti Maimets; Cecilia Rocchi; Reinier Bron; Sarah Pringle; Jeroen Kuipers; Ben N G Giepmans; Robert G J Vries; Hans Clevers; Gerald de Haan; Ronald van Os; Robert P Coppes

doi:10.1016/j.stemcr.2015.11.009

Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals

Martti Maimets, Cecilia Rocchi, Reinier Bron, Sarah Pringle, Jeroen Kuipers, Ben N G Giepmans, Robert G J Vries, Hans Clevers, Gerald de Haan, Ronald van Os, Robert P Coppes

99 Citationer (Scopus)

Abstract

Adult stem cells are the ultimate source for replenishment of salivary gland (SG) tissue. Self-renewal ability of stem cells is dependent on extrinsic niche signals that have not been unraveled for the SG. The ductal compartment in SG has been identified as the location harboring stem cells. Here, we report that rare SG ductal EpCAM(+) cells express nuclear β-catenin, indicating active Wnt signaling. In cell culture experiments, EpCAM(high) cells respond potently to Wnt signals stimulating self-renewal and long-term expansion of SG organoids, containing all differentiated SG cell types. Conversely, Wnt inhibition ablated long-term organoid cultures. Finally, transplantation of cells pre-treated with Wnt agonists into submandibular glands of irradiated mice successfully and robustly restored saliva secretion and increased the number of functional acini in vivo. Collectively, these results identify Wnt signaling as a key driver of adult SG stem cells, allowing extensive in vitro expansion and enabling restoration of SG function upon transplantation.

Originalsprog	Engelsk
Tidsskrift	Stem Cell Reports
Vol/bind	6
Udgave nummer	1
Sider (fra-til)	150-62
Antal sider	13
ISSN	2213-6711
DOI	https://doi.org/10.1016/j.stemcr.2015.11.009
Status	Udgivet - 12 jan. 2016
Udgivet eksternt	Ja

Adgang til dokumentet

10.1016/j.stemcr.2015.11.009

http://www.cell.com/article/S2213671115003458/pdfLicens: CC BY-NC-ND

Citationsformater

@article{8ee8d277893b42d89a13fe74bd7055f6,

title = "Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals",

abstract = "Adult stem cells are the ultimate source for replenishment of salivary gland (SG) tissue. Self-renewal ability of stem cells is dependent on extrinsic niche signals that have not been unraveled for the SG. The ductal compartment in SG has been identified as the location harboring stem cells. Here, we report that rare SG ductal EpCAM(+) cells express nuclear β-catenin, indicating active Wnt signaling. In cell culture experiments, EpCAM(high) cells respond potently to Wnt signals stimulating self-renewal and long-term expansion of SG organoids, containing all differentiated SG cell types. Conversely, Wnt inhibition ablated long-term organoid cultures. Finally, transplantation of cells pre-treated with Wnt agonists into submandibular glands of irradiated mice successfully and robustly restored saliva secretion and increased the number of functional acini in vivo. Collectively, these results identify Wnt signaling as a key driver of adult SG stem cells, allowing extensive in vitro expansion and enabling restoration of SG function upon transplantation.",

keywords = "Animals, Antigens, Neoplasm/metabolism, Cell Adhesion Molecules/metabolism, Cell Culture Techniques, Cell Proliferation, Cell Self Renewal, Cells, Cultured, Epithelial Cell Adhesion Molecule, Female, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Mice, Transgenic, Microscopy, Confocal, Microscopy, Electron, Transmission, Radiation Injuries, Experimental/therapy, Salivary Glands/cytology, Spheroids, Cellular/cytology, Stem Cell Transplantation/methods, Stem Cells/cytology, Time Factors, Wnt Signaling Pathway, beta Catenin/metabolism",

author = "Martti Maimets and Cecilia Rocchi and Reinier Bron and Sarah Pringle and Jeroen Kuipers and Giepmans, {Ben N G} and Vries, {Robert G J} and Hans Clevers and {de Haan}, Gerald and {van Os}, Ronald and Coppes, {Robert P}",

year = "2016",

month = jan,

day = "12",

doi = "10.1016/j.stemcr.2015.11.009",

language = "English",

volume = "6",

pages = "150--62",

journal = "Stem Cell Reports",

issn = "2213-6711",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals

AU - Maimets, Martti

AU - Rocchi, Cecilia

AU - Bron, Reinier

AU - Pringle, Sarah

AU - Kuipers, Jeroen

AU - Giepmans, Ben N G

AU - Vries, Robert G J

AU - Clevers, Hans

AU - de Haan, Gerald

AU - van Os, Ronald

AU - Coppes, Robert P

PY - 2016/1/12

Y1 - 2016/1/12

N2 - Adult stem cells are the ultimate source for replenishment of salivary gland (SG) tissue. Self-renewal ability of stem cells is dependent on extrinsic niche signals that have not been unraveled for the SG. The ductal compartment in SG has been identified as the location harboring stem cells. Here, we report that rare SG ductal EpCAM(+) cells express nuclear β-catenin, indicating active Wnt signaling. In cell culture experiments, EpCAM(high) cells respond potently to Wnt signals stimulating self-renewal and long-term expansion of SG organoids, containing all differentiated SG cell types. Conversely, Wnt inhibition ablated long-term organoid cultures. Finally, transplantation of cells pre-treated with Wnt agonists into submandibular glands of irradiated mice successfully and robustly restored saliva secretion and increased the number of functional acini in vivo. Collectively, these results identify Wnt signaling as a key driver of adult SG stem cells, allowing extensive in vitro expansion and enabling restoration of SG function upon transplantation.

AB - Adult stem cells are the ultimate source for replenishment of salivary gland (SG) tissue. Self-renewal ability of stem cells is dependent on extrinsic niche signals that have not been unraveled for the SG. The ductal compartment in SG has been identified as the location harboring stem cells. Here, we report that rare SG ductal EpCAM(+) cells express nuclear β-catenin, indicating active Wnt signaling. In cell culture experiments, EpCAM(high) cells respond potently to Wnt signals stimulating self-renewal and long-term expansion of SG organoids, containing all differentiated SG cell types. Conversely, Wnt inhibition ablated long-term organoid cultures. Finally, transplantation of cells pre-treated with Wnt agonists into submandibular glands of irradiated mice successfully and robustly restored saliva secretion and increased the number of functional acini in vivo. Collectively, these results identify Wnt signaling as a key driver of adult SG stem cells, allowing extensive in vitro expansion and enabling restoration of SG function upon transplantation.

KW - Animals

KW - Antigens, Neoplasm/metabolism

KW - Cell Adhesion Molecules/metabolism

KW - Cell Culture Techniques

KW - Cell Proliferation

KW - Cell Self Renewal

KW - Cells, Cultured

KW - Epithelial Cell Adhesion Molecule

KW - Female

KW - Mice, Inbred C57BL

KW - Mice, Inbred NOD

KW - Mice, Knockout

KW - Mice, SCID

KW - Mice, Transgenic

KW - Microscopy, Confocal

KW - Microscopy, Electron, Transmission

KW - Radiation Injuries, Experimental/therapy

KW - Salivary Glands/cytology

KW - Spheroids, Cellular/cytology

KW - Stem Cell Transplantation/methods

KW - Stem Cells/cytology

KW - Time Factors

KW - Wnt Signaling Pathway

KW - beta Catenin/metabolism

U2 - 10.1016/j.stemcr.2015.11.009

DO - 10.1016/j.stemcr.2015.11.009

M3 - Journal article

C2 - 26724906

SN - 2213-6711

VL - 6

SP - 150

EP - 162

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 1

ER -

Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater