title: Priming Wharton's jelly-derived mesenchymal stromal/stem cells with ROCK inhibitor improves recovery in an intracerebral hemorrhage model.
abstract: Mesenchymal stromal/stem cells (MSCs) have the potential to differentiate into neuron-like cells under specific conditions and to secrete paracrine factors for neuroprotection and regeneration. Previously, Rho-kinase inhibitors have been reported to potentiate differentiation of rodent bone marrow MSCs into neuron-like cells induced by CoCl2 (HIF-1α activation-mimicking agent). Here, a strategy of priming MSCs with fasudil, a Rho-kinase inhibitor, was investigated using Wharton's jelly-derived MSCs (WJ-MSCs) to improve recovery in a rat model of intracranial hemorrhage (ICH). In vitro culture of WJ-MSCs by co-treatment with fasudil (30 μM) and CoCl2 provoked morphological changes of WJ-MSCs into neuron-like cells and increased the expression of neuronal markers. Assessment of the secretion profiles showed that fasudil (30 μM) specifically increased glial cell line-derived neurotrophic factor (GDNF) among the secreted proteins at the transcription and secretion levels. For in vivo experiments, WJ-MSCs primed with fasudil (10 μM, exposure for 6 h) were transplanted into ICH rats with HIF-1α upregulation 1 week after injury, and neurological function was assessed via rotarod and limb placement tests for 7 weeks after transplantation. The group with WJ-MSCs primed with fasudil showed improved functional performance compared with the non-primed group. Accordingly, the primed group showed stronger expression of GDNF and higher levels of microtubule-associated protein 2 and neurofilament-H positive-grafted cells in the ICH lesion 3 weeks after transplantation compared with the non-primed group. Therefore, this work suggests that priming WJ-MSCs with fasudil is a possible application for enhanced cell therapy in stroke, with additional beneficial effect of up-regulation of GDNF.
authors.affiliation: Cancer Research Institute and Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, 137-701, Korea.
authors.forename: Hyun-Sun
authors.initials: HS
authors.lastname: Lee
authors.forename: Kwang S
authors.initials: KS
authors.lastname: Kim
authors.forename: Hee-Suk
authors.initials: HS
authors.lastname: Lim
authors.forename: Moran
authors.initials: M
authors.lastname: Choi
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Kim
authors.forename: Hyun-Young
authors.initials: HY
authors.lastname: Ahn
authors.forename: Jong-Chul
authors.initials: JC
authors.lastname: Shin
authors.forename: Young Ae
authors.initials: YA
authors.lastname: Joe
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000503:physiopathology / Q000628:therapy*; D003035:Cobalt / Q000494:pharmacology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018613:Microscopy, Confocal; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059631:Wharton Jelly / Q000166:cytology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D047428:Protein Kinase Inhibitors; D003035:Cobalt; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C018021:cobaltous chloride; C049347:fasudil
keywords: FASUDIL; GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR; INTRACEREBRAL HEMORRHAGE MODEL; MESENCHYMAL STROMAL/STEM CELL; ROCK INHIBITOR; TRANSPLANTATION