Open Access

Transplantation of Neural Crest-Like Cells Derived From Induced Pluripotent Stem Cells Improves Diabetic Polyneuropathy in Mice

Authors: Okawa, Tetsuji; Kamiya, Hideki; Himeno, Tatsuhito; Kato, Jiro; Seino, Yusuke; Fujiya, Atsushi; Kondo, Masaki; Tsunekawa, Shin; Naruse, Keiko; Hamada, Yoji; Ozaki, Nobuaki; Cheng, Zhao; Kito, Tetsutaro; Suzuki, Hirohiko; Ito, Sachiko; Oiso, Yutaka; Nakamura, Jiro; Isobe, Ken-Ichi

Source: Cell Transplantation, Volume 22, Number 10, October 2013 , pp. 1767-1783(17)

Publisher: Cognizant Communication Corporation

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Abstract:

Impaired vascularity and nerve degeneration are the most important pathophysiological abnormalities of diabetic polyneuropathy (DPN). Therefore, regeneration of both the vascular and nervous systems is required for the treatment of DPN. The neural crest (NC) is a transient embryonic structure in vertebrates that differentiates into a vast range of cells, including peripheral neurons, Schwann cells, and vascular smooth muscle cells. In this study, we investigated the ability of transplantation of NC-like (NCL) cells derived from aged mouse induced pluripotent stem (iPS) cells in the treatment of DPN. iPS cells were induced to differentiate into neural cells by stromal cell-derived inducing activity (SDIA) and subsequently supplemented with bone morphogenetic protein 4 to promote differentiation of NC lineage. After the induction, p75 neurotrophin receptor-positive NCL cells were purified using magnetic-activated cell sorting. Sorted NCL cells differentiated to peripheral neurons, glial cells, and smooth muscle cells by additional SDIA. NCL cells were transplanted into hind limb skeletal muscles of 16-week streptozotocin-diabetic mice. Nerve conduction velocity, current perception threshold, intraepidermal nerve fiber density, sensitivity to thermal stimuli, sciatic nerve blood flow, plantar skin blood flow, and capillary number-to-muscle fiber ratio were evaluated. Four weeks after transplantation, the engrafted cells produced growth factors: nerve growth factor, neurotrophin 3, vascular endothelial growth factor, and basic fibroblast growth factor. It was also confirmed that some engrafted cells differentiated into vascular smooth muscle cells or Schwann cell-like cells at each intrinsic site. The transplantation improved the impaired nerve and vascular functions. These results suggest that transplantation of NCL cells derived from iPS cells could have therapeutic effects on DPN through paracrine actions of growth factors and differentiation into Schwann cell-like cells and vascular smooth muscle cells.

Keywords: Aging; Diabetic polyneuropathy (DPN); Induced pluripotent stem (iPS) cells; Neural crest (NC); Regenerative medicine

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/096368912X657710

Affiliations: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan

Publication date: October 4, 2013

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.

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