Enhancing the Therapeutic Potential of CCL2-Overexpressing Mesenchymal Stem Cells in Acute Stroke

Abstract

Although intravenous administration of mesenchymal stem cells (MSCs) is effective for experimental stroke, low engraftment and the limited functional capacity of transplanted cells are critical hurdles for clinical applications. C–C motif chemokine ligand 2 (CCL2) is associated with neurological repair after stroke and delivery of various cells into the brain via CCL2/CCR2 (CCL2 receptor) interaction. In this study, after CCL2-overexpressing human umbilical cord-derived MSCs (hUC-MSCs) were intravenously transplanted with mannitol in rats with middle cerebral arterial occlusion, we compared the differences between four different treatment groups: mannitol + CCL2-overexpressing hUC-MSCs (CCL2-MSC), mannitol + naïve hUC-MSCs (M-MSC), mannitol only, and control. At four-weeks post-transplantation, the CCL2-MSC group showed significantly better functional recovery and smaller stroke volume relative to the other groups. Additionally, we observed upregulated levels of CCR2 in acute ischemic brain and the increase of migrated stem cells into these areas in the CCL2-MSC group relative to the M-MSC. Moreover, the CCL2-MSC group displayed increased angiogenesis and endogenous neurogenesis, decreased neuro-inflammation but with increased healing-process inflammatory cells relative to other groups. These findings indicated that CCL2-overexpressing hUC-MSCs showed better functional recovery relative to naïve hUC-MSCs according to the increased migration of these cells into brain areas of higher CCR2 expression, thereby promoting subsequent endogenous brain repair.

Inflammation-Mediated Angiogenesis in Ischemic Stroke

“…Additionally, MCP-1 is involved in neurological recovery after IS and delivers varieties of cells into the brain through MCP-1/CCR2 interplay. Moreover, after intravenous transplantation of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) with overexpression of MCP-1 in MCAO rats, angiogenesis was promoted in the ischemic penumbra region (Lee et al, 2020). This indicates that MCP-1-overexpressing hUC-MSCs distinctly repaired functional deficits in rats with MCAO by accelerating persistent increases in MCP-1 levels in brain tissue, promoting neurogenesis and angiogenesis and inhibiting neuroinflammation.…”

Potential Mechanisms and Perspectives in Ischemic Stroke Treatment Using Stem Cell Therapies

“…OPN expression upregulates and stimulates the migration of NSCs via CXCR4, resulting in an effective therapeutic effect after IS ( Rabenstein et al, 2015 ). During ischemia, C-C motif chemokine ligand 2 (CCL2), one of the most highly expressed chemokines, contributes to neurological repair; and the interaction between CCL2 and CCR2 (CCL2 receptor) enhances stem cell migration to the infarcted area, promoting subsequent brain repair ( Huang et al, 2018 ; Lee et al, 2020 ). TLRs are important mediators that cause neuroinflammation but are also involved in brain repair after IS.…”

Progress in Mesenchymal Stem Cell Therapy for Ischemic Stroke

“…Huang et al transplanted CCR2 transgenic MSCs in MCAO model animal and found that this kind of CCR2 overexpression MSCs can more effectively migrate to ischemic lesions and mediate the protection of blood-brain barrier and the more significant improvement of neural function [159]. In addition, Lee et al found that transplantation of CCL2 overexpressed MSCs resulted in a more significant increase in angiogenesis and neurogenesis and a more significant reduction in inflammatory response [160]. Moreover, the researchers also reported that overexpression of the neurogenic transcription factor neurogenin-1 can upregulate the expression of chemokine receptors CCR1, CCR2, and CXCR4 in MSCs, thus increasing the homing of MSCs to ischemic regions and promoting the further improvement of neural function [161].…”