Lipid-mediated Wnt protein stabilization enables serum-free culture of human organ stem cells

Nesrin Tüysüz, Louis van Bloois, Stieneke van den Brink, Harry Begthel, Monique M. A. Verstegen, Luis J. Cruz, Lijian Hui, Luc J. W. van der Laan, Jeroen de Jonge, Robert Vries, Eric Braakman, Enrico Mastrobattista, Jan J. Cornelissen, Hans Clevers and Derk ten Berge ()
Additional contact information
Nesrin Tüysüz: Erasmus University Medical Center
Louis van Bloois: Utrecht Institute for Pharmaceutical Sciences, Utrecht University
Stieneke van den Brink: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Cancer Genomics.nl and University Medical Center Utrecht
Harry Begthel: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Cancer Genomics.nl and University Medical Center Utrecht
Monique M. A. Verstegen: Erasmus University Medical Center
Luis J. Cruz: Experimental Molecular Imaging, Leiden University Medical Center
Lijian Hui: Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Luc J. W. van der Laan: Erasmus University Medical Center
Jeroen de Jonge: Erasmus University Medical Center
Robert Vries: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Cancer Genomics.nl and University Medical Center Utrecht
Eric Braakman: Erasmus University Medical Center
Enrico Mastrobattista: Utrecht Institute for Pharmaceutical Sciences, Utrecht University
Jan J. Cornelissen: Erasmus University Medical Center
Hans Clevers: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Cancer Genomics.nl and University Medical Center Utrecht
Derk ten Berge: Erasmus University Medical Center

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Wnt signalling proteins are essential for culture of human organ stem cells in organoids, but most Wnt protein formulations are poorly active in serum-free media. Here we show that purified Wnt3a protein is ineffective because it rapidly loses activity in culture media due to its hydrophobic nature, and its solubilization requires a detergent, CHAPS (3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate), that interferes with stem cell self-renewal. By stabilizing the Wnt3a protein using phospholipids and cholesterol as carriers, we address both problems: Wnt activity remains stable in serum-free media, while non-toxic carriers allow the use of high Wnt concentrations. Stabilized Wnt3a supports strongly increased self-renewal of organ and embryonic stem cells and the serum-free establishment of human organoids from healthy and diseased intestine and liver. Moreover, the lipophilicity of Wnt3a protein greatly facilitates its purification. Our findings remove a major obstacle impeding clinical applications of adult stem cells and offer advantages for all cell culture uses of Wnt3a protein.

Date: 2017
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DOI: 10.1038/ncomms14578

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