Preconditioned BMSC Promote de novo Nerve Regeneration: Potential application in therapy of enteric nerve injury/disorders and vascularized composite allotransplantation (VCA)

UNMET NEED

Injury or neurodegenerative disorders of the enteric nervous system (ENS) cause gastrointestinal dysfunctions for which there is no effective therapy, therefore new and effective treatments are urgently needed. Researchers from Johns Hopkins and Hospital of Tongji Medical College developed a novel approach to precondition bone marrow-derived mesenchymal stem cells (BMSC) for effective treatment of injury or neurodegenerative disorders of the enteric nervous system (ENS). This technology can be easily modified and applied in VCA to accelerate the functional recovery of grafted limbs or face, a major obstacle in VCA due to slow and inefficient nerve growth and renervation.

PROBLEM SOLVED

Using the benzalkonium chloride (BAC)-induced rat gastric denervation model, the researchers transplanted bone marrow-derived mesenchymal stem cells (BMSC) to determine whether they could promote ENS neuron regeneration and if so, to elucidate the mechanism of action. BMSC isolated from the bone marrow of 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. The grafted BMSC survived and migrated from the subserosa to the submucosa 28 days after transplantation. PGP9.5/NSE/HuC/D/Tuj1-positive neurons were regenerated de novo in the denervated pylorus grafted with preconditioned BMSC. BMSC transplantation restored both basal pyloric contractility and electric field stimulation-induced relaxation.

• MAJOR RESULTSIn vitro-preconditioned BMSCs promote de novo nerve regeneration and restore muscle contractility in pylorus-denervated rats through a GDNF positive feedback mechanism.
• A novel concept for the mechanism responsible for BMSC-induced neuron regeneration.
• Strong proof-of-principle for clinical application of BMSC-based therapy in ENS-related disorders.
• BMSC can be delivered endoscopically anywhere in the GI tract

ASSOCIATED PUBLICATIONS

■Stem Cells. 2015 Dec;33(12):3545-57 ■