Transplantation of neural crest-like cells derived from induced pluripotent stem cells improves diabetic polyneuropathy in mice.
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.
Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Tetsuji
T
Okawa
Hideki
H
Kamiya
Tatsuhito
T
Himeno
Jiro
J
Kato
Yusuke
Y
Seino
Atsushi
A
Fujiya
Masaki
M
Kondo
Shin
S
Tsunekawa
Keiko
K
Naruse
Yoji
Y
Hamada
Nobuaki
N
Ozaki
Zhao
Z
Cheng
Tetsutaro
T
Kito
Hirohiko
H
Suzuki
Sachiko
S
Ito
Yutaka
Y
Oiso
Jiro
J
Nakamura
Ken-Ichi
K
Isobe
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications; D003929:Diabetic Neuropathies / Q000209:etiology / Q000601:surgery*; D005434:Flow Cytometry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D009412:Nerve Fibers / Q000502:physiology; D020932:Nerve Growth Factor / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D016501:Neurites / Q000502:physiology; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D012584:Sciatic Nerve / Q000098:blood supply / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D055415:Bone Morphogenetic Protein 4; D020800:Receptor, Nerve Growth Factor; D042461:Vascular Endothelial Growth Factor A; D020932:Nerve Growth Factor