Lacrimal Gland Repair Using Progenitor Cells.
In humans, the lacrimal gland (LG) is the primary contributor to the aqueous layer of the tear film. Production of tears in insufficient quantity or of inadequate quality may lead to aqueous-deficiency dry eye (ADDE). Currently there is no cure for ADDE. The development of strategies to reliably isolate LG stem/progenitor cells from the LG tissue brings great promise for the design of cell replacement therapies for patients with ADDE. We analyzed the therapeutic potential of epithelial progenitor cells (EPCPs) isolated from adult wild-type mouse LGs by transplanting them into the LGs of TSP -1-/-mice, which represent a novel mouse model for ADDE. TSP-1-/-mice are normal at birth but progressively develop a chronic form of ocular surface disease, characterized by deterioration, inflammation, and secretory dysfunction of the lacrimal gland. Our study shows that, among c-kit-positive epithelial cell adhesion molecule (EpCAM+) populations sorted from mouse LGs, the c-kit+dim/EpCAM+/Sca1-/CD34-/CD45-cells have the hallmarks of an epithelial cell progenitor population. Isolated EPCPs express pluripotency factors and markers of the epithelial cell lineage Runx1 and EpCAM, and they form acini and ducts when grown in reaggregated three-dimensional cultures. Moreover, when transplanted into injured or "diseased" LGs, they engraft into acinar and ductal compartments. EPCP-injected TSP-1-/-LGs showed reduction of cell infiltration, differentiation of the donor EPCPs within secretory acini, and substantial improvement in LG structural integrity and function. This study provides the first evidence for the effective use of adult EPCP cell transplantation to rescue LG dysfunction in a model system. Stem Cells Translational Medicine 2017;6:88-98.
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.|Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California, USA.
Anastasia
A
Gromova
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.|Institute for Information Transmission Problems, Russian Academy of Sciences and A.N. Belozersky Institute of Physico-Chemical Biology of the Lomonosov Moscow State University, Moscow, Russia.
Dmitry A
DA
Voronov
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
Miya
M
Yoshida
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
Suharika
S
Thotakura
Department of Clinical Pharmacology, Flinders University, Bedford Park, South Australia, Australia.
Robyn
R
Meech
Department of Ophthalmology Harvard Medical School, Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
Darlene A
DA
Dartt
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
Helen P
HP
Makarenkova
D000818:Animals; D002454:Cell Differentiation; D003114:Colony-Forming Units Assay; D000071858:Epithelial Cell Adhesion Molecule / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D007765:Lacrimal Apparatus / Q000502:physiology*; D008810:Mice, Inbred C57BL; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012038:Regeneration; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000378:metabolism
D000071858:Epithelial Cell Adhesion Molecule; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit
Cell culture; Cell surface markers; Cell transplantation; Cellular therapy; Fluorescence-activated cell sorting; Gene expression; Tissue-specific stem cells; c-kit