Activation of ductal progenitor-like cells from adult human pancreas requires extracellular matrix protein signaling
Heather N. Zook,
Janine C. Quijano,
Jose A. Ortiz,
Cecile Donohue,
Kassandra Lopez,
Wendong Li,
Neslihan Erdem,
Kevin Jou,
Christiana J. Crook,
Isaac Garcia, Jr.,
Fouad Kandeel,
Enrique Montero,
Hsun Teresa Ku
Affiliations
Heather N. Zook
Irell & Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Janine C. Quijano
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Jose A. Ortiz
Irell & Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Cecile Donohue
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Kassandra Lopez
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Wendong Li
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Neslihan Erdem
Irell & Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Kevin Jou
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Christiana J. Crook
Irell & Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Isaac Garcia, Jr.
Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Fouad Kandeel
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Enrique Montero
Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Hsun Teresa Ku
Irell & Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA; Corresponding author
Summary: Ductal progenitor-like cells are a sub-population of ductal cells in the adult human pancreas that have the potential to contribute to regenerative medicine. However, the microenvironmental cues that regulate their activation are poorly understood. Here, we establish a 3-dimensional suspension culture system containing six defined soluble factors in which primary human ductal progenitor-like and ductal non-progenitor cells survive but do not proliferate. Expansion and polarization occur when suspension cells are provided with a low concentration (5% v/v) of Matrigel, a sarcoma cell product enriched in many extracellular matrix (ECM) proteins. Screening of ECM proteins identified that collagen IV can partially recapitulate the effects of Matrigel. Inhibition of integrin α1β1, a major collagen IV receptor, negates collagen IV- and Matrigel-stimulated effects. These results demonstrate that collagen IV is a key ECM protein that stimulates the expansion and polarization of human ductal progenitor-like and ductal non-progenitor cells via integrin α1β1 receptor signaling.
