• intensive care unit‑acquired weakness
• mesenchymal stem cells
• sepsis‑induced myopathy
• skeletal muscle atrophy

• Humans
• Sepsis/therapy
• Sepsis/complications
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cell Transplantation/methods
• Muscular Diseases/therapy
• Muscular Diseases/etiology
• Animals

• Conditioned medium
• Dermis
• Exosomes
• Integra matrix
• MSC
• Proteomic

• Humans
• Animals
• Mice
• Secretome
• Proteomics/methods
• Adipose Tissue/metabolism
• Mesenchymal Stem Cells/metabolism
• Wound Healing

• 456928/2013-8 Ministério da Ciência, Tecnologia e Inovação
• 465656/2014-5 Ministério da Ciência, Tecnologia e Inovação
• 407734/2018-0 Ministério da Ciência, Tecnologia e Inovação
• Finance Code 001 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
• The Wound Healing Society

• DogStem
• dogs
• intra-articular administration
• mesenchymal stem cell
• safety
• umbilical cord mesenchymal stem cell
• xenogeneic
• xenogeneic MSC transplantation

• Astrocyte ablation
• Cuprizone (CPZ)
• L-a-aminoadipate (L-AAA)
• Mesenchymal stem cells (MSCs)
• Multiple sclerosis (MS)
• Remyelination

• Animal models
• ICH
• Stem cells
• Updated, meta-analysis

• Stem cells research
• computational bioinformatics
• transcriptomics

• Cuprizone
• Demyelination
• Mesenchymal stem cell
• Transcranial direct current stimulation

Bronchopulmonary dysplasia (BPD) is not merely a chronic lung disease, but a systemic condition with multiple organs implications predominantly associated with hyperoxia exposure. Despite advances in current management strategies, limited progress has been made in reducing the BPD-related systemic damage. Meanwhile, although the protective effects of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) or their exosomes on hyperoxia-induced lung injury have been explored by many researchers, the underlying mechanism has not been addressed in detail, and few studies have focused on the therapeutic effect on systemic multiple organ injury.

To investigate whether hUC-MSC intratracheal administration could attenuate hyperoxia-induced lung, heart, and kidney injuries and the underlying regulatory mechanisms.

Neonatal rats were exposed to hyperoxia (80% O₂), treated with hUC-MSCs intratracheal (iT) or intraperitoneal (iP) on postnatal day 7, and harvested on postnatal day 21. The tissue sections of the lung, heart, and kidney were analyzed morphometrically. Protein contents of the bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) expression, and malondialdehyde (MDA) levels were examined. Pulmonary inflammatory cytokines were measured via enzyme-linked immunosorbent assay. A comparative transcriptomic analysis of differentially expressed genes (DEGs) in lung tissue was conducted via RNA-sequencing. Subsequently, we performed reverse transcription-quantitative polymerase chain reaction and western blot analysis to explore the expression of target mRNA and proteins related to inflammatory and oxidative responses.

iT hUC-MSCs administration improved pulmonary alveolarization and angiogenesis (P < 0.01, P < 0.01, P < 0.001, and P < 0.05 for mean linear intercept, septal counts, vascular medial thickness index, and microvessel density respectively). Meanwhile, treatment with hUC-MSCs iT ameliorated right ventricular hypertrophy (for Fulton’s index, P < 0.01), and relieved reduced nephrogenic zone width (P < 0.01) and glomerular diameter (P < 0.001) in kidneys. Among the beneficial effects, a reduction of BALF protein, MPO, and MDA was observed in hUC-MSCs groups (P < 0.01, P < 0.001, and P < 0.05 respectively). Increased pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-1β, and IL-6 expression observed in the hyperoxia group were significantly attenuated by hUC-MSCs administration (P < 0.01, P < 0.001, and P < 0.05 respectively). In addition, we observed an increase in anti-inflammatory cytokine IL-10 expression in rats that received hUC-MSCs iT compared with rats reared in hyperoxia (P < 0.05). Transcriptomic analysis showed that the DEGs in lung tissues induced by hyperoxia were enriched in pathways related to inflammatory responses, epithelial cell proliferation, and vasculature development. hUC-MSCs administration blunted these hyperoxia-induced dysregulated genes and resulted in a shift in the gene expression pattern toward the normoxia group. hUC-MSCs increased heme oxygenase-1 (HO-1), JAK2, and STAT3 expression, and their phosphorylation in the lung, heart, and kidney (P < 0.05). Remarkably, no significant difference was observed between the iT and iP administration.

iT hUC-MSCs administration ameliorates hyperoxia-induced lung, heart, and kidney injuries by activating HO-1 expression and JAK/STAT signaling. The therapeutic benefits of local iT and iP administration are equivalent.

• Mesenchymal stem cell
• Hyperoxia
• Multiple organ injury
• Bronchopulmonary dysplasia
• Heme oxygenase-1
• JAK/STAT pathway

Stroke is a leading cause of adult disability. In our previous study, transplantation of human umbilical mesenchymal stem cells (HUMSCs) in Wharton’s jelly in the acute phase of ischemic stroke promotes recovery in rats. Unfortunately, there is no cure for chronic stroke. Patients with chronic stroke can only be treated with rehabilitation or supportive interventions. This study aimed to investigate the potential of xenograft of HUMSCs for treating chronic stroke in rats. Rats were subjected to 90 min middle cerebral artery occlusion and then reperfusion to mimic ischemic cerebral stroke. On day 14 following stroke, HUMSCs were transplanted into the damaged cerebral cortex. The motor function in rats of the Stroke + HUMSCs group exhibited significant improvement compared to that of the Stroke + Saline group, and the trend persisted until day 56 post stroke. The cerebral cortex changes were tracked using magnetic resonance imaging, showing that cerebral atrophy was found starting on day 7 and was reduced significantly in rats receiving HUMSCs compared to that in the Stroke + Saline group from day 21 to day 56. HUMSCs were found to be existed in the rats’ cerebral cortex on day 56, with signs of migration. The grafted HUMSCs did not differentiate into neurons or astrocytes and may release cytokines to improve neuroprotection, decrease inflammation and increase angiogenesis. Our results demonstrate that xeno-transplantation of HUMSCs has therapeutic benefits for chronic ischemic stroke. Most importantly, patients do not need to use their own HUMSCs, which is a gospel thing for clinical patients.

• MRI
• Wharton’s jelly
• angiogenesis
• cerebral ischemia
• chronic stroke
• neurologic deficit
• neuroprotection
• transplantation
• umbilical mesenchymal stem cells
• xenograft

Abdominal aortic aneurysm (AAA) is life-threatening, surgical treatment is currently the only clinically available intervention for the disease. Mesenchymal stem cells (MSCs) have presented eligible immunomodulatory and regenerative abilities which showed favorable therapeutic efficacy in various cardiovascular diseases. However, current evidence summarizing the effectiveness of MSCs for AAA is lacking. Thus, a meta-analysis and systematic review was necessary to be performed to assess the therapeutic efficacy of MSCs for AAA in preclinical studies.

Comprehensive literature search restricted in English was conducted in PubMed, Cochrane Library, EBSCO, EMBASE and Web of Science from inception to Oct 2021. The primary outcomes were parameters about aortic diameter change during MSCs intervention. The secondary outcomes included elastin content and expression level of inflammatory cytokines, matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). Data were extracted and analyzed independently by two authors. The meta package with random effects model was used to calculate the pooled effect size and 95% confidence intervals in R (version 4.0.2).

Meta-analysis of 18 included studies demonstrated that MSCs intervention has significant therapeutic effects on suppressing aortic diameter enlargement compared with the control group (diameter, SMD = − 1.19, 95% CI [− 1.47, − 0.91]; diameter change ratio, SMD = − 1.36, 95% CI [− 1.72, − 1.00]). Subgroup analysis revealed differences between MSCs and control group regarding to cell type, intervention route and cell compatibility. Moreover, the meta-analysis also showed that MSCs intervention had a significant effect on preserving aortic elastin content, reducing MCP-1, TNF-α, IL-6, MMP-2/9 and increasing TIMP-1/2 expression level compared with control group.

Our results suggested that MSC intervention is effective in AAA by suppressing aortic diameter enlargement, reducing elastin degradation, and modulating local immunoinflammatory reactions. These results are important for the systemic application of MSCs as a potential treatment candidate for AAA in further animal experiments and clinical trials.

The online version contains supplementary material available at 10.1186/s13287-022-02755-w.

• Abdominal aortic aneurysm
• Cell therapy
• Mesenchymal stem cell
• Meta-analysis
• Preclinical studies

• brain plasticity
• extracellular vesicles
• recovery
• stem cell
• stroke
• trophic factors

• Correlative microscopy
• Electron microscopy
• Magnetic fields
• SPION
• Stem cell therapy
• Stroke

• Adipocytes
• Animals
• Brain
• Magnetic Fields
• Magnetic Resonance Imaging/methods
• Magnetite Nanoparticles/chemistry
• Rats
• Stem Cells
• Stroke/therapy

• Alteplase
• GAP-43
• GFAP
• acute cerebral infarction

• PLX3397
• demyelination
• mesenchymal stem cells
• microglia
• multiple sclerosis

• Aminopyridines/administration & dosage
• Aminopyridines/pharmacology
• Animals
• Behavior, Animal/drug effects
• Biomarkers/metabolism
• CX3C Chemokine Receptor 1/metabolism
• Calcium-Binding Proteins/metabolism
• Chemokine CX3CL1/metabolism
• Corpus Callosum/pathology
• Corpus Callosum/ultrastructure
• Cuprizone
• Demyelinating Diseases/chemically induced
• Demyelinating Diseases/pathology
• Demyelinating Diseases/therapy
• Disease Models, Animal
• Glial Fibrillary Acidic Protein/metabolism
• Injections, Intraventricular
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/drug effects
• Mice, Inbred C57BL
• Microfilament Proteins/metabolism
• Microglia/drug effects
• Microglia/pathology
• Myelin Sheath/drug effects
• Myelin Sheath/metabolism
• Myelin Sheath/pathology
• Pyrroles/administration & dosage
• Pyrroles/pharmacology
• Mice

Stem cell transplantation offers promise in the treatment of ischemic stroke. Here we utilized systematic review, meta-analysis, and meta-regression to study the biological effect of stem cell treatments in animal models of ischemic stroke. A total of 98 eligible publications were included by searching PubMed, EMBASE, and Web of Science from inception to August 1, 2020. There are about 141 comparisons, involving 5,200 animals, that examined the effect of stem cell transplantation on neurological function and infarct volume as primary outcome measures in animal models for stroke. Stem cell-based therapy can improve both neurological function (effect size, −3.37; 95% confidence interval, −3.83 to −2.90) and infarct volume (effect size, −11.37; 95% confidence interval, −12.89 to −9.85) compared with controls. These results suggest that stem cell therapy could improve neurological function deficits and infarct volume, exerting potential neuroprotective effect for experimental ischemic stroke, but further clinical studies are still needed.

• ischemic stroke
• middle cerebral artery occlusion
• neuroprotection
• pre-clinical systematic review
• stem cell-based therapy

• Demyelinating disease
• Extracellular vesicles
• Neurodegenerative diseases

• Aging
• Comorbidity
• Diabetes
• Hyperlipidemia
• Hypertension
• Inflammation
• Ischemic stroke
• Neuroprotection
• Obesity
• Stroke models

• Aging
• Animals
• Comorbidity
• Disease Models, Animal
• Humans
• Ischemic Stroke/therapy
• Translational Research, Biomedical
• Treatment Outcome

• R01 NS059962 NINDS NIH HHS
• R01 NS103094 NINDS NIH HHS
• R01 NS109816 NINDS NIH HHS

Drug abuse is a major global health and economic problem. However, there are no pharmacological treatments to effectively reduce the compulsive use of most drugs of abuse. Despite exerting different mechanisms of action, all drugs of abuse promote the activation of the brain reward system, with lasting neurobiological consequences that potentiate subsequent consumption. Recent evidence shows that the brain displays marked oxidative stress and neuroinflammation following chronic drug consumption. Brain oxidative stress and neuroinflammation disrupt glutamate homeostasis by impairing synaptic and extra-synaptic glutamate transport, reducing GLT-1, and system X_c⁻ activities respectively, which increases glutamatergic neurotransmission. This effect consolidates the relapse-promoting effect of drug-related cues, thus sustaining drug craving and subsequent drug consumption. Recently, promising results as experimental treatments to reduce drug consumption and relapse have been shown by (i) antioxidant and anti-inflammatory synthetic molecules whose effects reach the brain; (ii) natural biomolecules secreted by mesenchymal stem cells that excel in antioxidant and anti-inflammatory properties, delivered via non-invasive intranasal administration to animal models of drug abuse and (iii) potent anti-inflammatory microRNAs and anti-miRNAs which target the microglia and reduce neuroinflammation and drug craving. In this review, we address the neurobiological consequences of brain oxidative stress and neuroinflammation that follow the chronic consumption of most drugs of abuse, and the current and potential therapeutic effects of antioxidants and anti-inflammatory agents and biomolecules to reduce these drug-induced alterations and to prevent relapse.

• drug addiction
• neuroinflammation
• oxidative stress
• treatment

• Functional recovery
• Stem cells
• Stroke

• Exosome
• lung spheroid cell
• regenerative medicine
• stem cell

• R01 HL146153 NHLBI NIH HHS
• R01 HL144002 NHLBI NIH HHS
• R01 HL147357 NHLBI NIH HHS
• R01 HL123920 NHLBI NIH HHS
• R01 HL137093 NHLBI NIH HHS

• adipose
• angiogenesis
• differentiation
• stem
• vascularization

• Adipose Tissue/cytology
• Animals
• Cell Differentiation
• Cell Proliferation
• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/physiology
• Neovascularization, Physiologic

• inflammation
• ischemia
• mesenchymal stem cells
• oligodendrogenesis
• stroke
• therapy

• Animals
• Behavior, Animal
• Brain/metabolism
• Brain/pathology
• Brain/physiopathology
• Cells, Cultured
• Disease Models, Animal
• Female
• Infarction, Middle Cerebral Artery/metabolism
• Infarction, Middle Cerebral Artery/pathology
• Infarction, Middle Cerebral Artery/physiopathology
• Infarction, Middle Cerebral Artery/surgery
• Inflammation/metabolism
• Inflammation/pathology
• Inflammation/physiopathology
• Inflammation/prevention & control
• Inflammation Mediators/metabolism
• Interferon-gamma/pharmacology
• Ischemic Stroke/metabolism
• Ischemic Stroke/pathology
• Ischemic Stroke/physiopathology
• Ischemic Stroke/surgery
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/metabolism
• Motor Activity
• Neurogenesis
• Oligodendroglia/metabolism
• Oligodendroglia/pathology
• Open Field Test
• Rats, Sprague-Dawley
• Recovery of Function

• R01 AG062251 NIA NIH HHS
• T32 AG057468 NIA NIH HHS
• R01 AG033570 NIA NIH HHS
• R01 AG060238 NIA NIH HHS
• R21 AG061628 NIA NIH HHS
• T32 HL007692 NHLBI NIH HHS
• P01 AI089556 NIAID NIH HHS
• National Institute on Aging
• Center for Clinical and Translational Science
• National Heart, Lung, and Blood Institute
• American Heart Association
• National Institute of Allergy and Infectious Diseases

• Integra artificial skin
• biocompatible materials
• mesenchymal stem cells
• regenerative medicine
• tissue engineering
• wound healing

• cardiovascular disorders
• stem cell
• tissue engineering

Over 50% of acute stroke patients have hyperglycemia, which is associated with a poorer prognosis and outcome. Our aim was to investigate the impact of hyperglycemia on behavioral recovery and brain repair of delivered human adipose tissue-derived mesenchymal stem cells (hAD-MSCs) in a rat model of permanent middle cerebral artery occlusion (pMCAO).

Hyperglycemia was induced in rats by the administration of nicotinamide and streptozotocin. The rats were then subjected to stroke by a pMCAO model. At 48 h post-stroke, 1 × 10⁶ hAD-MSCs or saline were intravenously administered. We evaluated behavioral outcome, infarct size by MRI, and brain plasticity markers by immunohistochemistry (glial fibrillary acidic protein [GFAP], Iba-1, synaptophysin, doublecortin, CD-31, collagen-IV, and α-smooth muscle actin [α-SMA]).

The hyperglycemic group exhibited more severe neurological deficits; lesion size and diffusion coefficient were larger compared with the non-hyperglycemic rats. GFAP, Iba-1, and α-SMA were increased in the hyperglycemic group. The hyperglycemic rats administered hAD-MSCs at 48 h after pMCAO had improved neurological impairment. Although T2-MRI did not show differences in lesion size between groups, the rADC values were lower in the treated group. Finally, the levels of GFAP, Iba-1, and arterial wall thickness were lower in the treated hyperglycemic group than in the nontreated hyperglycemic group at 6 weeks post-stroke.

Our data suggest that rats with hyperglycemic ischemic stroke exhibit increased lesion size and impaired brain repair processes, which lead to impairments in behavioral recovery after pMCAO. More importantly, hAD-MSC administration induced better anatomical tissue preservation, associated with a good behavioral outcome.

The online version of this article (10.1186/s13287-019-1322-x) contains supplementary material, which is available to authorized users.

• Adipose tissue
• Behavioral outcome
• Brain repair
• Experimental model
• Hyperglycemia
• Mesenchymal stem cells

As the second cause of death and cognitive decline in industrialized countries, stroke is a major burden for society. Vascular risks factors such as hypertension and diabetes are involved in most stroke patients, aggravate stroke severity, but are still poorly taken into account in preclinical studies. Microangiopathy and sustained inflammation are exacerbated, likely explaining the severity of stroke in those patients. We sought to demonstrate that intravenous administration of human adipose derived-mesenchymal stem cells (hADMSC) that have immunomodulatory properties, could accelerate sensorimotor recovery, prevent long-term spatial memory impairment and promote neurogenesis, in diabetic or hypertensive mice, subjected to permanent middle cerebral artery occlusion (pMCAo). Diabetic (streptozotocin IP) or hypertensive (L-NAME in drinking water) male C57Bl6 mice subjected to pMCAo, were treated by hADMSC (500,000 cells IV) 2 days after cerebral ischemia induction. Infarct volume, neurogenesis, microglial/macrophage density, T-lymphocytes density, astrocytes density, and vessel density were monitored 7 days after cells injection and at 6 weeks. Neurological sensorimotor deficit and spatial memory were assessed until 6 weeks post-stroke. Whatever the vascular risk factor, hADMSC showed no effect on functional sensorimotor recovery or cognitive decline prevention at short or long-term assessment, nor significantly modified neurogenesis, microglial/macrophage, T-lymphocytes, astrocytes, and vessel density. This work is part of a European program (H2020, RESSTORE). We discuss the discrepancy of our results with those obtained in rats and the optimal cell injection time frame, source and type of cells according to the species stroke model. A comprehensive understanding of the mechanisms preventing recovery should help for successful clinical translation, but first could allow identifying good and bad responders to cell therapy in stroke.

• adipose tissue
• behavior
• cell therapy
• cognitive decline
• inflammation
• stroke

• Cuprizone
• Demyelination
• Glial cells
• Mesenchymal stem cells
• Multiple sclerosis
• Trophic factors

• Animals
• Chemokine CX3CL1/metabolism
• Cuprizone
• Cytokines/metabolism
• Demyelinating Diseases/chemically induced
• Demyelinating Diseases/metabolism
• Male
• Mesenchymal Stem Cells
• Mice
• Neuroglia/metabolism
• Transforming Growth Factor beta/metabolism

Adipose stromal/stem cells (ASCs) are an ideal cell type for regenerative medicine applications, as they can easily be harvested from adipose tissue in large quantities. ASCs have excellent proliferation, differentiation, and immunoregulatory capacities that have been demonstrated in numerous studies. Great interest and investment have been placed in efforts to exploit the allogeneic use and immunomodulatory and anti-inflammatory effects of ASCs. However, bridging the gap between in vitro and in vivo studies and moving into clinical practice remain a challenge. For the clinical translation of ASCs, several issues must be considered, including how to characterise such a heterogenic cell population and how to ensure their safety and efficacy. This review explores the different phases of in vitro and preclinical ASC characterisation and describes the development of appropriate potency assays. In addition, good manufacturing practice requirements are discussed, and cell-based medicinal products holding marketing authorisation in the European Union are reviewed. Moreover, the current status of clinical trials applying ASCs and the patent landscape in the field of ASC research are presented. Overall, this review highlights the applicability of ASCs for clinical cell therapies and discusses their potential.

• aging
• comorbidity
• diabetes
• hyperglycemia
• hypertension
• mesenchymal
• obesity
• stroke

• cuprizone model
• immunomodulation
• mesenchymal stem cells
• microglial phenotype
• multiple sclerosis

• cell therapy
• combination therapy
• functional outcome
• mechanisms
• rehabilitation
• stroke
• translational research

• ASC
• DSC
• MSC
• cell scratching
• cutaneous repair
• isolation
• mesenchymal stem cells
• regeneration

• Adipose-derived stem cells
• Cell transplantation
• Cerebral infarction
• Macrophage

• Adipose tissue-derived stem cells
• Allogeneic
• Autologous
• Focal cerebral infarct
• Transplantation

• Adipose stem/stromal cells
• Adult stem cells
• Autologous stem cell transplantation
• Cellular therapy
• Mesenchymal stem cells
• Stromal vascular fraction cells
• Tissue regeneration

We investigated the effects of intra-articular injections of alginate-microencapsulated adipose tissue-derived mesenchymal stem cells (ASCs) during osteoarthritis (OA) development in a rabbit model of anterior cruciate ligament transection (ACLT). We induced OA in mature New Zealand white rabbits by bilateral ACLT. Stifle joints were categorised into four groups according to intra-articular injection materials. Alginate microbeads and microencapsulated ASCs were prepared using the vibrational nozzle technology. Two weeks after ACLT, the rabbits received three consecutive weekly intra-articular injections of 0.9% NaCl, alginate microbeads, ASCs, or microencapsulated ASCs, into each joint. Nine weeks after ACLT, we euthanised the rabbits and collected bilateral femoral condyles for macroscopic, histological, and immunohistochemical analyses. Macroscopic evaluation using the modified OA Research Society International (OARSI) score and total cartilage damage score showed that cartilage degradation on the femoral condyle was relatively low in the microencapsulated-ASC group. Histological analysis of the lateral femoral condyles indicated that microencapsulated ASCs had significant chondroprotective effects. Immunohistochemically, the expression of MMP-13 after the articular cartilage damage was relatively low in the microencapsulated-ASC-treated stifle joints. During the development of experimental OA, as compared to ASCs alone, intra-articular injection of microencapsulated ASCs significantly decreased the progression and extent of OA.

• adipose-derived mesenchymal stem cells
• biodistribution
• colitis
• efficacy
• intraperitoneal therapy

• MAP kinases
• NGF
• PC12 pheochromocytoma cells
• antioxidants
• growth factors
• ischemia
• lipid peroxidation
• neuroprotection
• oxygen-glucose deprivation and reoxygenation injury
• stem cells

Mild therapeutic hypothermia has been shown to mitigate cerebral ischemia, reduce cerebral edema, and improve the prognosis of patients with cerebral ischemia. Adipose-derived stem cell-based therapy can decrease neuronal death and infiltration of inflammatory cells, exerting a neuroprotective effect. We hypothesized that the combination of mild therapeutic hypothermia and adipose-derived stem cells would be neuroprotective for treatment of stroke. A rat model of transient middle cerebral artery occlusion was established using the nylon monofilament method. Mild therapeutic hypothermia (33°C) was induced after 2 hours of ischemia. Adipose-derived stem cells were administered through the femoral vein during reperfusion. The severity of neurological dysfunction was measured by a modified Neurological Severity Score Scaling System. The area of the infarct lesion was determined by 2,3,5-triphenyltetrazolium chloride staining. Apoptotic neurons were detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. The regeneration of microvessels and changes in the glial scar were detected by immunofluorescence staining. The inflammatory responses after ischemic brain injury were evaluated by in situ staining using markers of inflammatory cells. The expression of inflammatory cytokines was measured by reverse transcription-polymerase chain reaction. Compared with mild therapeutic hypothermia or adipose-derived stem cell treatment alone, their combination substantially improved neurological deficits and decreased infarct size. They synergistically reduced the number of TUNEL-positive cells and glial fibrillary acidic protein expression, increased vascular endothelial growth factor levels, effectively reduced inflammatory cell infiltration and down-regulated the mRNA expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α and interleukin-6. Our findings indicate that combined treatment is a better approach for treating stroke compared with mild therapeutic hypothermia or adipose-derived stem cells alone.

• adipose-derived stem cells
• brain injury
• cerebral resuscitation
• combination therapy
• mild therapeutic hypothermia
• nerve regeneration
• neural regeneration
• neuronal cell death
• neuroprotection
• rats
• stroke
• transient middle cerebrum artery occlusion

• Exosome
• angiogenesis
• ischemic stroke

• SC1 HL134212 NHLBI NIH HHS

• Animals
• Brain Ischemia/therapy
• Mesenchymal Stem Cell Transplantation/adverse effects
• Mesenchymal Stem Cell Transplantation/methods
• Stroke/therapy
• Time Factors

• Cell engineering
• Clinical
• Ischemic stroke
• Neuroprotection
• Preclinical
• Stem cells

• Animals
• Brain Ischemia/complications
• Clinical Trials as Topic/methods
• Humans
• Stem Cell Transplantation/methods
• Stem Cells/physiology
• Stroke/etiology
• Stroke/surgery

Stem cell transplantation has been documented to promote functional recovery in animal models of stroke; however, the underlying mechanisms are not yet fully understood. As netrin-1 and its receptor deleted in colorectal cancer (DCC) are important regulators in neuronal and vascular activities, the present study attempted to explore whether netrin-1 and DCC are involved in the neuroprotection of stem cell-based therapies in a rat ischemic stroke model.

Adult male Sprague–Dawley rats were subjected to a transient middle cerebral artery occlusion (MCAO) and subsequently received an intra-arterial injection of 2 × 10⁶ PKH26-labeled adipose-derived stem cells (ADSCs) or saline 24 h later. Neurological function was evaluated by behavioral tests before the rats were sacrificed at days 7 and 14 after MCAO. The migration of ADSCs and regeneration of neuronal fibers and blood vessels were determined by immunofluorescence staining. The expression of netrin-1 and DCC was analyzed by Western blot and immunofluorescence staining.

ADSC transplantation significantly improved the neurological recovery at days 7 and 14, and noticeably promoted the regeneration of neuronal fibers and blood vessels in the peri-infarct cortex at day 14. PKH26-labeled ADSCs located mainly in the peri-infarct area at days 7 and 14. In ADSC-treated rats, the expression of netrin-1 and DCC significantly increased in the peri-infarct cortex at days 7 and 14. Immunofluorescence staining showed that netrin-1 was mainly expressed by neuronal perikaryal in the peri-infarct cortex, and DCC was mainly expressed by neuronal fibers and was present around the blood vessels in the peri-infarct cortex.

These findings suggest that ADSC transplantation facilitates the regeneration of neuronal fibers and blood vessels in the peri-infarct cortex and improves neurological functions, which may be attributed, at least in part, to the involvement of upregulated netrin-1 and DCC in the remodeling of neuronal and vascular networks in the peri-infarct cortex.

• Adipose-derived stem cells
• DCC
• Netrin-1
• Neurological recovery
• Regeneration
• Stroke

• Adipose-derived mesenchymal stem cells (AD-MSC)
• Fibroblast growth factor 1 (FGF1)
• Stroke
• Transfection
• Transient middle cerebral artery occlusion (tMCAO)

• Adipocytes/cytology
• Adipocytes/metabolism
• Adipocytes/transplantation
• Adipose Tissue/cytology
• Adipose Tissue/metabolism
• Animals
• Cell Differentiation
• Cerebrum/metabolism
• Cerebrum/pathology
• Disease Models, Animal
• Fibroblast Growth Factor 1/genetics
• Fibroblast Growth Factor 1/metabolism
• Gene Expression
• Humans
• Infarction, Middle Cerebral Artery/genetics
• Infarction, Middle Cerebral Artery/metabolism
• Infarction, Middle Cerebral Artery/pathology
• Infarction, Middle Cerebral Artery/therapy
• Infusions, Intravenous
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Radiopharmaceuticals/administration & dosage
• Rats
• Rats, Wistar
• Recovery of Function
• Rotarod Performance Test
• Stroke/genetics
• Stroke/metabolism
• Stroke/pathology
• Stroke/therapy
• Technetium Tc 99m Exametazime/administration & dosage
• Transgenes