ZIGIR, a Granule-Specific Zn2+ Indicator, Reveals Human Islet α Cell Heterogeneity
Ebrahim H. Ghazvini Zadeh,
ZhiJiang Huang,
Jing Xia,
Daliang Li,
Howard W. Davidson,
Wen-hong Li
Affiliations
Ebrahim H. Ghazvini Zadeh
Departments of Cell Biology and Biochemistry, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9039, USA
ZhiJiang Huang
Departments of Cell Biology and Biochemistry, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9039, USA
Jing Xia
Departments of Cell Biology and Biochemistry, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9039, USA; Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
Daliang Li
Departments of Cell Biology and Biochemistry, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9039, USA
Howard W. Davidson
Barbara Davis Center for Diabetes, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA
Wen-hong Li
Departments of Cell Biology and Biochemistry, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9039, USA; Corresponding author
Summary: Numerous mammalian cells contain abundant Zn2+ in their secretory granules, yet available Zn2+ sensors lack the desired specificity and sensitivity for imaging granular Zn2+. We developed a fluorescent zinc granule indicator, ZIGIR, that possesses numerous desired properties for live cell imaging, including >100-fold fluorescence enhancement, membrane permeability, and selective enrichment to acidic granules. The combined advantages endow ZIGIR with superior sensitivity and specificity for imaging granular Zn2+. ZIGIR enables separation of heterogenous β cells based on their insulin content and sorting of mouse islets into pure α cells and β cells. In human islets, ZIGIR facilitates sorting of endocrine cells into highly enriched α cells and β cells, reveals unexpectedly high Zn2+ activity in the somatostatin granule of some δ cells, and uncovers variation in the glucagon content among human α cells. We expect broad applications of ZIGIR for studying Zn2+ biology and Zn2+-rich secretory granules and for engineering β cells with high insulin content for treating diabetes.
