Intraarterial transplantation of human umbilical cord blood mononuclear cells in hyperacute stroke improves vascular function

Stem Cell Research & Therapy, Apr 2017

Background Human umbilical cord blood (hUCB) cell therapy is a promising treatment for ischemic stroke. The effects of hyperacute stem cell transplantation on cerebrovascular function in ischemic stroke are, however, not well understood. This study evaluated the effects of hyperacute intraarterial transplantation of hUCB mononuclear cells (MNCs) on cerebrovascular function in stroke rats using serial magnetic resonance imaging (MRI). Methods HUCB MNCs or vehicle were administered to stroke rats via the internal carotid artery immediately after reperfusion at 60 min following ischemia onset. Lesion volumes were longitudinally evaluated by MRI on days 0, 2, 14, and 28 after stroke, accompanied by behavioral tests. Cerebral blood flow (CBF) and cerebrovascular reactivity were measured by perfusion MRI and CO2 functional MRI (fMRI) at 28 days post-stroke; corresponding vascular morphological changes were also detected by immunohistology in the same animals. Results We found that CBF to the stroke-affected region at 28 days was improved (normalized CBF value: 1.41 ± 0.30 versus 0.49 ± 0.07) by intraarterial transplantation of hUCB MNCs in the hyperacute stroke phase, compared to vehicle control. Cerebrovascular reactivity within the stroke-affected area, measured by CBF fMRI, was also increased (35.2 ± 3.5% versus 12.8 ± 4.3%), as well as the corresponding cerebrovascular density. Some engrafted cells appeared with microvascular-like morphology and stained positive for von Willebrand Factor (an endothelial cell marker), suggesting they differentiated into endothelial cells. Some engrafted cells also connected to host endothelial cells, suggesting they interacted with the host vasculature. Compared to the vehicle group, infarct volume at 28 days in the stem cell treated group was significantly smaller (160.9 ± 15.7 versus 231.2 ± 16.0 mm3); behavioral deficits were also markedly reduced by stem cell treatment at day 28 (19.5 ± 1.0% versus 30.7 ± 4.7% on the foot fault test; 68.2 ± 4.6% versus 86.6 ± 5.8% on the cylinder test). More tissue within initial perfusion-diffusion mismatch was rescued in the treatment group. Conclusions Intraarterial hUCB MNC transplantation during the hyperacute phase of ischemic stroke improved cerebrovascular function and reduced behavioral deficits and infarct volume.

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Intraarterial transplantation of human umbilical cord blood mononuclear cells in hyperacute stroke improves vascular function

Huang et al. Stem Cell Research & Therapy Intraarterial transplantation of human umbilical cord blood mononuclear cells in hyperacute stroke improves vascular function Lei Huang 0 Yichu Liu 3 Jianfei Lu 0 Bianca Cerqueira 0 3 Vivek Misra 2 Timothy Q. Duong 0 1 0 Research Imaging Institute, University of Texas Health Science Center , San Antonio, Texas , USA 1 Radiology, Stony Brook Medicine , Stony Brook, NY , USA 2 Department of Neurology, University of Texas Health Science Center , San Antonio, Texas , USA 3 Department of Biomedical Engineering, University of Texas , San Antonio, Texas , USA Background: Human umbilical cord blood (hUCB) cell therapy is a promising treatment for ischemic stroke. The effects of hyperacute stem cell transplantation on cerebrovascular function in ischemic stroke are, however, not well understood. This study evaluated the effects of hyperacute intraarterial transplantation of hUCB mononuclear cells (MNCs) on cerebrovascular function in stroke rats using serial magnetic resonance imaging (MRI). Methods: HUCB MNCs or vehicle were administered to stroke rats via the internal carotid artery immediately after reperfusion at 60 min following ischemia onset. Lesion volumes were longitudinally evaluated by MRI on days 0, 2, 14, and 28 after stroke, accompanied by behavioral tests. Cerebral blood flow (CBF) and cerebrovascular reactivity were measured by perfusion MRI and CO2 functional MRI (fMRI) at 28 days post-stroke; corresponding vascular morphological changes were also detected by immunohistology in the same animals. Conclusions: Intraarterial hUCB MNC transplantation during the hyperacute phase of ischemic stroke improved cerebrovascular function and reduced behavioral deficits and infarct volume. Umbilical cord blood cell; Stroke; Cell transplantation; CBF; MRI; Vasoreactivity - Background Cell therapy is a promising treatment for ischemic stroke. Several preclinical stroke studies have shown beneficial effects following transplantation of stem cells derived from various sources, including embryonic tissue [1], adult bone marrow [2], adipose [3], and umbilical cord blood (UCB) [4, 5]. Amongst these, UCB cells offer several advantages because they are more readily available and have no associated graft-versus-host reactions [6]. Unlike cells derived from embryonic sources, there are no ethical issues with using cells derived from UCB. UCB cells have been used clinically to treat hematological malignancies for more than two decades with a good safety record [7]. Transplantation of human UCB (hUCB) mononuclear cells (MNCs) and their different subcomponents (i.e., hematopoietic stem cells (HSCs), mesenchymal stem cell (MSCs), and endothelial progenitor cells (EPCs)) have also been shown to be effective in animal models of ischemic stroke [4, 5, 8]. Most preclinical studies evaluated cell administration 24 h or later after stroke, and reported outcomes using behavioral assessment and histology, and a few used T2-weighted magnetic resonance imaging (MRI) to measure infarct volume [4, 5, 9, 10]. In addition to quantifying lesion volume and the tissue at-risk (i.e., “perfusion-diffusion” mismatch) [11, 12] in a longitudinal manner, MRI can also be used to measure cerebral blood flow (CBF) and CBF responses to physiological and functional challenges, providing a noninvasive method to study neuron-vascular coupling and hemodynamic regulation after stroke and during recovery [12]. CBF and cerebrovascular reactivity are known to be perturbed after stroke [12–14], and recovery of CBF and cerebrovascular reactivity plays an important role in functional recovery in ischemic stroke [15]. However, the effects of hUCB MNC transplantation on vascular function in vivo (i.e., CBF, cerebrovascular reactivity, and the underlying vascular changes) are not well understood. The goal of this study was to evaluate the effects of hyperacute intraarterial transplantation of hUCB MNCs on cerebral vascular function in a rat model of focal cerebral ischemia. We hypothesize that such treatment improves CBF and cerebrovascular reactivity on the stroke-affected region, with reducing behavioral deficits and infarct volume. The intraarterial delivery method was intended to mimic the clinical condition in which stem cell treatment could be administered following mechanical thrombectomy where a catheter is already in place [16, 17]. The effects of intraarterial stem cell infusion on the ischemic lesion volume were longitudinally evaluated by MRI on days 0, 2, 14, and 28 days following stroke, accompanied with behavioral tests. CBF and cerebrovascular reactivity were measured by perfusion MRI and CO2 fMRI at 28 days post-stroke; corresponding vascular morphological changes were also detected by immunohistology in the same animals. Methods All experiments followed guideline and regulations consistent with the Guide for the Care and Use of Laboratory Animals, Public Health Service Policy on Humane Care and Use (...truncated)


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Lei Huang, Yichu Liu, Jianfei Lu, Bianca Cerqueira, Vivek Misra, Timothy Q. Duong. Intraarterial transplantation of human umbilical cord blood mononuclear cells in hyperacute stroke improves vascular function, Stem Cell Research & Therapy, 2017, pp. 74, Volume 8, Issue 1, DOI: 10.1186/s13287-017-0529-y