Research reportExpression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells
Introduction
Neural stem or progenitor cells reside in the subventricular zone (SVZ) throughout the life of mammals [19], [20], and are capable of giving rise to neurons, astrocytes and other cell types [17]. In addition, brain injuries such as focal ischemia have been shown to induce neurogenesis in the SVZ [23], [49]. Previous studies have demonstrated that bone marrow stromal cells (MSCs) administered intravenously after stroke migrate selectively and target damaged brain, increase angiogenesis, enhance neurogenesis, promote neural stem cell proliferation and migration and improve functional recovery [9], [12], [27]. However, the molecular mechanisms underlying these MSC-evoked neurorestorative and brain plasticity processes remain obscure.
The phenotypic state of a cell is influenced by a variety of extracellular signals. Insulin-like growth factor 1 (IGF-1) is a polypeptide growth factor that plays an important role in normal brain growth and development [2], [18], and has been shown to have neurotrophic and neuroprotective effects in vitro and in vivo in different lesion models [7], [16], [21], [28], [40], [42]. Its pleiotropic effects range from classical trophic actions on neurons such as housekeeping or anti-apoptotic/pro-survival effects to modulation of brain-barrier permeability, neuronal excitability, increasing neurogenesis and participating in brain angiogenesis [7], [46]. The binding of IGF-1 to IGF-I receptor (IGF-1R) activates the receptor tyrosine kinase (RTK) activity, which can lead to changes in gene expression, cell phenotype, cell proliferation, differentiation and migration [22].
Therefore, in the present study, we sought to investigate the molecular mechanisms underlying the human bone marrow stromal cell (hMSC) effect on both neural cell proliferation and migration after stroke in rat, by measuring the expression levels of IGF-1, IGF-1R mRNA and proteins in response to hMSC treatment.
Section snippets
Materials and methods
All experimental procedures have been approved by the Institutional Animal Care and Use Committee.
Administration of hMSCs improves neurological function
The severity of MCAo was balanced between the hMSC- and control-treated groups (p=0.97). hMSCs by time interaction was detected (p-value for interaction=0.03). Treatment at 1 day after MCAo with hMSCs marginally improved functional recovery at 7 days (p=0.07), significantly improved functional recovery, as evidence by improved mNSS at 14 (p<0.01), 21 and 30 days (p<0.05) compared with ischemia rats treated with PBS (Table 1).
Administration of hMSCs increases brain expression of IGF-1 mRNA
RT-PCR showed IGF-1 mRNA level was very low in normal rats, but there
Discussion
Neurological recovery after stroke likely involves a cascade of events, including angiogenesis, neurogenesis and synaptogenesis. The results of the present study demonstrate that treatment of stroke with intravenously administered hMSCs after induction of focal cerebral ischemia achieved a significant neurogenic effect. The endogenous factors which promote neurogenesis are not yet identified. Because cell proliferation, differentiation and survival are under the control of growth factors in
Acknowledgements
This work was supported by NIH grants PO1 NS42345 and RO1 NS45041. hMSCs were supplied by Cognate Therapeutics. The authors thank Cynthia Roberts and Lei Wang for their technical assistance and Deborah Jewell for secretarial support.
References (50)
The IGF-I receptor in cancer research
Exp. Cell Res.
(1999)- et al.
Inhibition of IGF-1 receptor expression and signaling—novel strategies for anti-metastatic strategies
Biochem. Pharmacol.
(2000) - et al.
Treatment of neural injury with marrow stromal cells
Lancet Neurol.
(2002) - et al.
Mesenchymal stem cells: biology and potential clinical uses
Exp. Hematol.
(2000) - et al.
Insulin-like growth factor-1 and post-ischemic brain injury
Prog. Neurobiol.
(2003) - et al.
Neuronal migration
Mech. Dev.
(2001) - et al.
Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion
Neurosci. Lett.
(2001) - et al.
Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice
Exp. Neurol.
(2004) - et al.
The receptor for the type I insulin-like growth factor and its ligands regulate multiple cellular functions that impact on metastasis
Surg. Oncol. Clin. N. Am.
(2001) - et al.
Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia
Neuroscience
(2001)