Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model.
Neuroplasticity subsequent to functional angiogenesis is an important goal for cell-based therapy of ischemic neural tissues. At present, the cellular and molecular mechanisms involved are still not well understood. In this study, we isolated mesenchymal stem cells (MSCs) from Wharton's jelly (WJ) to obtain clonally expanded human umbilical cord-derived mesenchymal stem cells (HUCMSCs) with multilineage differentiation potential. Experimental rats receiving intracerebral HUCMSC transplantation showed significantly improved neurological function compared to vehicle-treated control rats. Cortical neuronal activity, as evaluated by proton MR spectroscopy (1H-MRS), also increased considerably in the transplantation group. Transplanted HUCMSCs migrated towards the ischemic boundary zone and differentiated into glial, neuronal, doublecortin+, CXCR4+, and vascular endothelial cells to enhance neuroplasticity in the ischemic brain. In addition, HUCMSC transplantation promoted the formation of new vessels to increase local cortical blood flow in the ischemic hemisphere. Modulation by stem cell-derived macrophage/microglial interactions, and increased beta1-integrin expression, might enhance this angiogenic architecture within the ischemic brain. Inhibition of beta1-integrin expression blocked local angiogenesis and reduced recovery from neurological deficit. In addition, significantly increased modulation of neurotrophic factor expression was also found in the HUCMSC transplantation group. In summary, regulation of beta1-integrin expression plays a critical role in the plasticity of the ischemic brain after the implantation of HUCMSCs.
Ding
Dah-Ching
DC
Graduate Institute of Medical Science, School of Medicine, Buddhist Tzu Chi General Hospital, Tzu-Chi University, Department of Obstetrics and Gynecology, Hualien, Taiwan 970.
Shyu
Woei-Cherng
WC
Chiang
Ming-Fu
MF
Lin
Shinn-Zong
SZ
Chang
Ying-Chen
YC
Wang
Hsiao-Jung
HJ
Su
Ching-Yuan
CY
Li
Hung
H
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply; D002545:Brain Ischemia / Q000628:therapy*; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D000089662:Doublecortin Protein; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D019012:Integrin beta1 / Q000096:biosynthesis*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology; D018613:Microscopy, Confocal; D018919:Neovascularization, Physiologic; D009473:Neuronal Plasticity / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000628:therapy*; D017154:Stromal Cells / Q000637:transplantation; D014470:Umbilical Cord / Q000166:cytology; D015854:Up-Regulation
C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D019012:Integrin beta1