Matrix Degradability Contributes to the Development of Salivary Gland Progenitor Cells with Secretory Functions
| Author(s) | Metkari, Apoorva S. | |
| Author(s) | Fowler, Eric W. | |
| Author(s) | Witt, Robert L. | |
| Author(s) | Jia, Xinqiao | |
| Date Accessioned | 2023-09-14T15:52:28Z | |
| Date Available | 2023-09-14T15:52:28Z | |
| Publication Date | 2023-07-12 | |
| Description | This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Applied Materials and Interfaces, copyright © 2023 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acsami.3c03064. This article will be embargoed until 07/12/2024. | |
| Abstract | Synthetic matrices that are cytocompatible, cell adhesive, and cell responsive are needed for the engineering of implantable, secretory salivary gland constructs to treat radiation induced xerostomia or dry mouth. Here, taking advantage of the bioorthogonality of the Michael-type addition reaction, hydrogels with comparable stiffness but varying degrees of degradability (100% degradable, 100DEG; 50% degradable, 50DEG; and nondegradable, 0DEG) by cell-secreted matrix metalloproteases (MMPs) were synthesized using thiolated HA (HA-SH), maleimide (MI)-conjugated integrin-binding peptide (RGD-MI), and MI-functionalized peptide cross-linkers that are protease degradable (GIW-bisMI) or nondegradable (GIQ-bisMI). Organized multicellular structures developed readily in all hydrogels from dispersed primary human salivary gland stem cells (hS/PCs). As the matrix became progressively degradable, cells proliferated more readily, and the multicellular structures became larger, less spherical, and more lobular. Immunocytochemical analysis showed positive staining for stem/progenitor cell markers CD44 and keratin 5 (K5) in all three types of cultures and positive staining for the acinar marker α-amylase under 50DEG and 100DEG conditions. Quantitatively at the mRNA level, the expression levels of key stem/progenitor markers KIT, KRT5, and ETV4/5 were significantly increased in the degradable gels as compared to the nondegradable counterparts. Western blot analyses revealed that imparting matrix degradation led to >3.8-fold increase in KIT expression by day 15. The MMP-degradable hydrogels also promoted the development of a secretary phenotype, as evidenced by the upregulation of acinar markers α-amylase (AMY), aquaporin-5 (AQP5), and sodium-potassium chloride cotransporter 1 (SLC12A2). Collectively, we show that cell-mediated matrix remodeling is necessary for the development of regenerative pro-acinar progenitor cells from hS/PCs. | |
| Sponsor | This work was supported in part by the National Institutes of Health (NIDCR R01 DE029655, NIDCD, R01DC014461), National Science Foundation (NSF, DMR 2243648), and Delaware Bioscience Center for Advanced Technology (DE-CAT 12A00448). The authors also acknowledge the use of facilities and instrumentation supported by NSF through the University of Delaware Materials Research Science and Engineering Center (DMR 2011824) and by the National Institute of General Medical Sciences (P20 GM104316) from the National Institutes of Health. Microscopy access was supported by grants from the NIH-NIGMS (P20 GM103446), the NSF (IIA-1301765), and the State of Delaware. We thank Drs. Jeffrey Caplan and Sylvain Le Marchand for their expert assistance in confocal imaging and image analysis. We thank Sanofi/Genzyme for generously providing HA. | |
| Citation | Metkari, Apoorva S., Eric W. Fowler, Robert L. Witt, and Xinqiao Jia. “Matrix Degradability Contributes to the Development of Salivary Gland Progenitor Cells with Secretory Functions.” ACS Applied Materials & Interfaces 15, no. 27 (July 12, 2023): 32148–61. https://doi.org/10.1021/acsami.3c03064. | |
| ISSN | 1944-8252 | |
| URL | https://udspace.udel.edu/handle/19716/33301 | |
| Language | en_US | |
| Publisher | ACS Applied Materials and Interfaces | |
| Keywords | salivary gland | |
| Keywords | stem/progenitor cells | |
| Keywords | matrix degradation | |
| Keywords | MMP | |
| Keywords | c-KIT | |
| Title | Matrix Degradability Contributes to the Development of Salivary Gland Progenitor Cells with Secretory Functions | |
| Type | Article |
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