Intravenous Injection of Clinical Grade Human MSCs After Experimental Stroke: Functional Benefit and Microvascular Effect

Cell Transplant. 2016 Dec 13;25(12):2157-2171. doi: 10.3727/096368916X691132. Epub 2016 Feb 26.

Abstract

Stroke is the leading cause of disability in adults. Many current clinical trials use intravenous (IV) administration of human bone marrow-derived mesenchymal stem cells (BM-MSCs). This autologous graft requires a delay for ex vivo expansion of cells. We followed microvascular effects and mechanisms of action involved after an IV injection of human BM-MSCs (hBM-MSCs) at a subacute phase of stroke. Rats underwent a transient middle cerebral artery occlusion (MCAo) or a surgery without occlusion (sham) at day 0 (D0). At D8, rats received an IV injection of 3 million hBM-MSCs or PBS-glutamine. In a longitudinal behavioral follow-up, we showed delayed somatosensory and cognitive benefits 4 to 7 weeks after hBM-MSC injection. In a separate longitudinal in vivo magnetic resonance imaging (MRI) study, we observed an enhanced vascular density in the ischemic area 2 and 3 weeks after hBM-MSC injection. Histology and quantitative polymerase chain reaction (qPCR) revealed an overexpression of angiogenic factors such as Ang1 and transforming growth factor-1 (TGF-1) at D16 in hBM-MSC-treated MCAo rats compared to PBS-treated MCAo rats. Altogether, delayed IV injection of hBM-MSCs provides functional benefits and increases cerebral angiogenesis in the stroke lesion via a release of endogenous angiogenic factors enhancing the stabilization of newborn vessels. Enhanced angiogenesis could therefore be a means of improving functional recovery after stroke.

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Brain Ischemia / pathology
  • Brain Ischemia / therapy
  • Cell- and Tissue-Based Therapy
  • Disease Models, Animal
  • Humans
  • Immunohistochemistry
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / pathology
  • Magnetic Resonance Imaging
  • Male
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / physiology
  • Microvessels / metabolism
  • Microvessels / pathology
  • Neovascularization, Physiologic / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function
  • Stroke / pathology*
  • Stroke / therapy
  • Transforming Growth Factor beta2 / metabolism

Substances

  • Transforming Growth Factor beta2