title: In Vitro Conditioned Bone Marrow-Derived Mesenchymal Stem Cells Promote De Novo Functional Enteric Nerve Regeneration, but Not Through Direct-Transdifferentiation.
abstract: Injury or neurodegenerative disorders of the enteric nervous system (ENS) cause gastrointestinal dysfunctions for which there is no effective therapy. This study, using the benzalkonium chloride-induced rat gastric denervation model, aimed to determine whether transplantation of bone marrow-derived mesenchymal stem cells (BMSC) could promote ENS neuron regeneration and if so, to elucidate the mechanism. Fluorescently labeled BMSC, isolated from either WT (BMSC labeled with bis-benzimide [BBM]) or green fluorescent protein (GFP)-transgenic rats, were preconditioned in vitro using fetal gut culture media containing glial cell-derived neurotrophic factor (GDNF), and transplanted subserosally into the denervated area of rat pylorus. In the nerve-ablated pylorus, grafted BMSC survived and migrated from the subserosa to the submucosa 28 days after transplantation, without apparent dedifferentiation. A massive number of PGP9.5/NSE/HuC/D/Tuj1-positive (but GFP- and BBM-negative) neurons were effectively regenerated in denervated pylorus grafted with preconditioned BMSC, suggesting that they were regenerated de novo, not originating from trans-differentiation of the transplanted BMSC. BMSC transplantation restored both basal pyloric contractility and electric field stimulation-induced relaxation. High levels of GDNF were induced in both in vitro-preconditioned BMSC as well as the previously denervated pylorus after transplantation of preconditioned BMSC. Thus, a BMSC-initiated GDNF-positive feedback mechanism is suggested to promote neuron regeneration and growth. In summary, we have demonstrated that allogeneically transplanted preconditioned BMSC initiate de novo regeneration of gastric neuronal cells/structures that in turn restore gastric contractility in pylorus-denervated rats. These neuronal structures did not originate from the grafted BMSC. Our data suggest that preconditioned allogeneic BMSC may have therapeutic value in treating enteric nerve disorders.
authors: Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.|Department of Medicine/GI Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Rong
authors: R
authors: Lin
authors: Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.|Department of Medicine/GI Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Zhen
authors: Z
authors: Ding
authors: Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.|Division of Gastroenterology, Qingdao Municipal Hospital, Qingdao, People's Republic of China.
authors: Huan
authors: H
authors: Ma
authors: Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Huiying
authors: H
authors: Shi
authors: Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Yuanjun
authors: Y
authors: Gao
authors: Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Wei
authors: W
authors: Qian
authors: Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Weina
authors: W
authors: Shi
authors: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Zhaoli
authors: Z
authors: Sun
authors: Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Xiaohua
authors: X
authors: Hou
authors: Department of Medicine/GI Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Xuhang
authors: X
authors: Li
mesh_terms: D064591:Allografts; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D017615:Enteric Nervous System / Q000502:physiology*; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009416:Nerve Regeneration; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic
keywords: Bone marrow stromal cells; Bone marrow-derived mesenchymal stem cell; Neural differentiation neural induction; Neural stem cell; Stem cell transplantation; Tissue regeneration