Regulated and Reversible Induction of Adult Human β-cell Replication

• Published in: Diabetes (New York, N.Y.) Vol. 61; no. 2; pp. 418 - 424
• Main Authors: TAKANE, Karen K, KLEINBERGER, Jeffery W, SALIM, Fatimah G, FIASCHI-TAESCH, Nathalie M, STEWART, Andrew F
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.2012
• Subjects: Adenoviridae - genetics; Adult; Biological and medical sciences; Cell proliferation; Cell Proliferation - drug effects; Control; Cyclin D1 - genetics; Cyclin D1 - physiology; Cyclin-Dependent Kinase 6 - genetics; Cyclin-Dependent Kinase 6 - physiology; Diabetes. Impaired glucose tolerance; Doxycycline - pharmacology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Humans; Insulin-Secreting Cells - physiology; Islet Studies; Medical sciences; Pancreatic beta cells; Physiological aspects; Endocrinopathy; Human; Diabetes mellitus; Langerhans islet; Replication; β Cell; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db11-0580

Induction of proliferation in adult human β-cells is challenging. It can be accomplished by introduction of cell cycle molecules such as cyclin-dependent kinase 6 (cdk6) and cyclin D1, but their continuous overexpression raises oncogenic concerns. We attempted to mimic normal, transient, perinatal human β-cell proliferation by delivering these molecules in a regulated and reversible manner. Adult cadaveric islets were transduced with doxycycline (Dox)-inducible adenoviruses expressing cdk6 or cyclin D1. End points were cdk6/cyclin D1 expression and human β-cell proliferation, survival, and function. Increasing doses of Dox led to marked dose- and time-related increases in cdk6 and cyclin D1, accompanied by a 20-fold increase in β-cell proliferation. Notably, Dox withdrawal resulted in a reversal of both cdk6 and cyclin D1 expression as well as β-cell proliferation. Re-exposure to Dox reinduced both cdk/cyclin expression and proliferation. β-Cell function and survival were not adversely affected. The adenoviral tetracycline (tet)-on system has not been used previously to drive human β-cell proliferation. Human β-cells can be induced to proliferate or arrest in a regulated, reversible manner, temporally and quantitatively mimicking the transient perinatal physiological proliferation that occurs in human β-cells.