The fusion of bone-marrow-derived proinsulin-expressing cells with nerve cells underlies diabetic neuropathy

Departments of ^*Molecular Genetics in Medicine and ^¶Anatomy and Divisions of ^†Neurology and ^**Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan; ^‡Division of Diabetes, Endocrinology, and Metabolism, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030; and ^∥Department of Medicine, University of Chicago, Chicago, IL 60637

Communicated by Salih J. Wakil, Baylor College of Medicine, Houston, TX, July 7, 2005 (received for review June 9, 2005)

Abstract

Diabetic neuropathy is the most common microvascular complication of diabetes. Here we show that, in streptozotocin-induced diabetic rodents with neuropathy, a subpopulation of bone-marrow-derived cells marked by proinsulin expression migrates to and fuses with neurons in the sciatic nerve and dorsal root ganglion (DRG), resulting in neuronal dysfunction and accelerated apoptosis. The absence or presence of proinsulin expression, which identifies the fusion cells, and not the disease state (nondiabetic vs. diabetic) of the rats from which the DRG neurons are isolated determines whether the DRG neurons show normal or abnormal calcium homeostasis and apoptosis. These results suggest that bone-marrow-derived cells may play an important role in the pathogenesis of diabetic complications.

Footnotes

↵ †† To whom correspondence should be addressed. E-mail: lchan{at}bcm.tmc.edu.
↵ § T.T., H.K., and M.F. contributed equally to this work.
Author contributions: T.T., H. Kojima, M.F., A.K., H.Y., and L.C. designed research; T.T., H. Kojima, M.F., K.M., J.O., and H. Kimura performed research; M.H. contributed new reagents/analytic tools; T.T., H. Kojima, M.F., A.K., H. Kimura, H.Y., and L.C. analyzed data; H. Kojima, M.F., and L.C. wrote the paper; and L.C. directed the entire project.
Abbreviations: BMD, bone marrow derived; STZ, streptozotocin; DRG, dorsal root ganglion; BMT, bone marrow transplantation; LCM, laser-capture microdissection; NF, neurofilament; MIP, mouse insulin I gene promoter.