Author Correction: Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition.

In the version of Supplementary Fig. 3c originally published with this Article, the authors mistakenly duplicated a blot from Supplementary Fig. 3b. The correct versions of these figures are shown below. In addition, two independent repeats of the experiments presented in Supplementary Figs. 3b and 3c, showing results consistent with those originally reported, have been deposited in Figshare ( 10.6084/m9.figshare.7545263 ).

STAT3-coordinated migration facilitates the dissemination of diffuse large B-cell lymphomas.

The motile characteristics and mechanisms that drive the dissemination of diffuse large B-cell lymphoma (DLBCL) are elusive. Here, we show that DLBCL initiates dissemination through activating STAT3-mediated amoeboid migration. Mechanistically, STAT3 activates RHOH transcription, which competes with the RhoGDP dissociation inhibitor RhoGDIγ to activate RhoA. In addition, activated STAT3 regulates microtubule dynamics and releases ARHGEF2 to activate RhoA. Both the JAK inhibitor ruxolitinib and the microtubule stabilizer Taxol suppress DLBCL cell dissemination in vivo. A clinical DLBCL sample analysis shows that STAT3-driven amoeboid movement is particularly important for the transition from stage I to stage II. This study elucidates the mechanism of DLBCL dissemination and progression and highlights the potential of combating advanced DLBCL with a JAK/STAT inhibitor or microtubule stabilizer to reduce DLBCL motility; these findings may have a great impact on the development of patient-tailored treatments for DLBCL.

PD-L1 expression is associated with p16INK4A expression in non-oropharyngeal head and neck squamous cell carcinoma.

PD-L1 expression is critical in helping tumor cells evade the immune system. However, the level of PD-L1 expression in non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC) and its association with patient prognosis remains unclear. A retrospective clinicopathological analysis was performed on 106 patients with non-OPHNSCC diagnosed between 2007 and 2014. In the current study, tissue arrays from paraffin-embedded non-OPHNSCC samples obtained from patients were constructed, and PD-L1 and p16INK4A expression were determined using immunohistochemistry. Systemic inflammatory factors, including C-reactive protein, serum white blood cell, neutrophil, monocyte and lymphocyte counts were also analyzed. The current study demonstrated that PD-L1 was overexpressed in 32.1% (34/106) and p16INK4A in 20.8% (22/106) of patients. The expression of PD-L1 was associated with p16INK4A expression (P<0.01) but was not associated with levels of systemic inflammatory factors. Tumor stage was determined to be a significant prognostic value (stage I/II vs. III/IV, P=0.03), however, PD-L1, p16INK4A or other clinicopathological factors were not. The current study identified an association between PD-L1 and p16INK4A expression in non-OPHNSCC. This may facilitate the development of anti-PD1/PDL1 therapies to treat patients with head and neck cancer.

Lymphotoxin-ß Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer.

Purpose: In head and neck squamous cell carcinoma (HNSCC), the incidence of RAS mutation, which is the major cause of cetuximab resistance, is relatively rare compared with the other types of cancers, and the mechanism mediating acquired resistance is unclear compared with the driver gene mutation-mediated de novo resistance. Here, we investigated the driver gene mutation-independent mechanism for cetuximab resistance in HNSCC.Experimental Design: We used the in vitro-selected and in vivo-selected cetuximab-resistant sublines of HNSCC cell lines for investigating the mechanism of acquired resistance to cetuximab. Zebrafish model was applied for evaluating the synergistic effect of combinatory drugs for overcoming cetuximab resistance.Results: The cetuximab-resistant HNSCC cells undergo a Snail-induced epithelial-mesenchymal transition. Mechanistically, Snail induces the expression of lymphotoxin-ß (LTß), a TNF superfamily protein that activates NF-κB, and protein arginine methyltransferase 1 (PRMT1), an arginine methyltransferase that methylates EGFR. LTß interacts with methylated EGFR to promote its ligand-binding ability and dimerization. Furthermore, LTß activates the NF-κB pathway through a LTß receptor-independent mechanism. Combination of an EGFR tyrosine kinase inhibitor and a NF-κB inhibitor effectively suppressed cetuximab-resistant HNSCC and interfering with the EGFR-LTß interaction reverses resistance.Conclusions: Our findings elucidate the mechanism of driver gene mutations-independent mechanism of acquired resistance to cetuximab in HNSCC and also provide potential strategies for combating cetuximab resistance. Clin Cancer Res; 23(15); 4388-401. ©2017 AACR.

Acetylation of snail modulates the cytokinome of cancer cells to enhance the recruitment of macrophages.

Snail is primarily known as a transcriptional repressor that induces epithelial-mesenchymal transition by suppressing adherent proteins. Emerging evidence suggests that Snail can act as an activator; however, the mechanism and biological significance are unclear. Here, we found that CREB-binding protein (CBP) is the critical factor in Snail-mediated target gene transactivation. CBP interacts with Snail and acetylates Snail at lysine 146 and lysine 187, which prevents the repressor complex formation. We further identified several Snail-activated targets, including TNF-α, which is also the upstream signal for Snail acetylation, and CCL2 and CCL5, which promote the recruitment of tumor-associated macrophages. Here, we present our results on the mechanism by which Snail induces target gene transactivation to remodel the tumor microenvironment.

Histone modification patterns correlate with patient outcome in oral squamous cell carcinoma.

BACKGROUND: Patterns of global histone modifications have been suggested to be predictors of clinical outcome in many cancers. However, the role of global histone modification patterns in oral squamous cell carcinoma (OSCC) is unclear. METHODS: A retrospective clinicopathologic analysis was undertaken of 186 patients with oral squamous cell carcinoma who received complete ablative surgical treatment. Tissue arrays were made from those paraffin-embedded OSCC samples and examined by immunohistochemistry for histone 3 lysine 4 acetylation (H3K4ac), histone 3 lysine 18 acetylation (H3K18ac), histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 9 trimethylation (H3K9me3), and histone 3 lysine 27 trimethylation (H3K27me3). RESULTS: A low level of H3K4ac and a high level of H3K27me3 were associated with advanced T status, N status, tumor stage, and perineural invasion. They were also correlated with cancer-specific survival (CSS) and disease-free survival (DFS). The 5-year CSS and DFS in H3K4ac(low) vs. H3K4ac(high) were 74.8% versus 92.5% (P = .010), and 51.4% versus 76.2% (P = .001), respectively. The 5-year CSS and DFS in H3K27me3(low) versus H3K27me3(high) were 94.7% versus 62.3% (P < .001) and 76.4% versus 32.3% (P < .001), respectively. We also found improved prediction for DFS after combining the H3K4ac(low) and H3K27me3(high) profiles and comparing the scores with the other modification patterns (P < .0001). CONCLUSIONS: This research demonstrates the potential prognostic utility of global histone modification analysis for OSCC.

Role of stress-inducible protein-1 in recruitment of bone marrow derived cells into the ischemic brains.

Stress-inducible protein-1 (STI-1) is the proposed ligand for the cellular prion protein (PrP(C) ), which is thought to facilitate recovery following stroke. Whether STI-1 expression is affected by stroke and how its signalling facilitates recovery remain elusive. Brain slices from patients that died of ischemic stroke were collected for STI-1 immunohistochemistry. These findings were compared to results from cell cultures, mice with or without the PrP(C) knockout, and rats. Based on these findings, molecular and pharmacological interventions were administered to investigate the underlying mechanisms and to test the possibility for therapy in experimental stroke models. STI-1 was upregulated in the ischemic brains from humans and rodents. The increase in STI-1 expression in vivo was not cell-type specific, as it was found in neurons, glia and endothelial cells. Likewise, this increase in STI-1 expression can be mimicked by sublethal hypoxia in primary cortical cultures (PCCs) in vitro, and appear to have resulted from the direct binding of the hypoxia inducible factor-1α (HIF-1α) to the STI-1 promoter. Importantly, this STI-1 signalling promoted bone marrow derived cells (BMDCs) proliferation and migration in vitro and recruitment to the ischemic brain in vivo, and augmenting its signalling facilitated neurological recovery in part by recruiting BMDCs to the ischemic brain. Our results thus identified a novel mechanism by which ischemic insults can trigger a self-protective mechanism to facilitate recovery.

Role of HIF-1α-activated Epac1 on HSC-mediated neuroplasticity in stroke model.

Exchange protein activated by cAMP-1 (Epac1) plays an important role in cell proliferation, cell survival and neuronal signaling, and activation of Epac1 in endothelial progenitor cells increases their homing to ischemic muscles and promotes neovascularization in a model of hind limb ischemia. Moreover, upregulation of Epac1 occurs during organ development and in diseases such as myocardial hypertrophy, diabetes, and Alzheimer's disease. We report here that hypoxia upregulated Epac1 through HIF-1α induction in the CD34-immunosorted human umbilical cord blood hematopoietic stem cells (hUCB(34)). Importantly, implantation of hUCB(34) subjected to hypoxia-preconditioning (HP-hUCB(34)) improved stroke outcome, more than did implantation of untreated hUCB(34), in rodents subjected to cerebral ischemia, and this required Epac1-to-matrix metalloprotease (MMP) signaling. This improved therapeutic efficacy correlated with better engraftment and differentiation of these cells in the ischemic host brain. In addition, more than did implantation of untreated HP-hUCB(34), implantation of HP-hUCB(34) improved cerebral blood flow into the ischemic brain via induction of angiogenesis, facilitated proliferation/recruitment of endogenous neural progenitor cells in the ischemic brain, and promoted neurite outgrowth following cerebral ischemia. Consistent with our proposed role of Epac1-to-MMP signaling in hypoxia-preconditioning, the above mentioned effects of implanting HP-hUCB(34) could be abolished by pharmacological inhibition and genetic disruption/deletion of Epac1 or MMPs. We have discovered a HIF-1α-to-Epac1-to-MMP signaling pathway that is required for the improved therapeutic efficacy resulting from hypoxia preconditioning of hUCB(34) in vitro prior to their implantation into the host brain in vivo.

Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition.

The epithelial-mesenchymal transition (EMT), one of the main mechanisms underlying development of cancer metastasis, induces stem-like properties in epithelial cells. Bmi1 is a polycomb-group protein that maintains self-renewal, and is frequently overexpressed in human cancers. Here, we show the direct regulation of BMI1 by the EMT regulator, Twist1. Furthermore, Twist1 and Bmi1 were mutually essential to promote EMT and tumour-initiating capability. Twist1 and Bmi1 act cooperatively to repress expression of both E-cadherin and p16INK4a. In patients with head and neck cancers, increased levels of both Twist1 and Bmi1 correlated with downregulation of E-cadherin and p16INK4a, and was associated with the worst prognosis. These results suggest that Twist1-induced EMT and tumour-initiating capability in cancer cells occurs through chromatin remodelling, which leads to unfavourable clinical outcomes.

Nonsenescent Hsp27-upregulated MSCs implantation promotes neuroplasticity in stroke model.

Cellular senescence induces changes in cellular physiology, morphology, proliferative capacity, and gene expression. Stem cell senescence might be one of the major issues of limited efficacy of stem cell transplantation. In this study, we demonstrated that implantation of human umbilical cord mesenchymal stem cells (hUCMSCs) cultured in human umbilical cord serum (hUCS) significantly enhanced neuroplasticity and angiogenesis in stroke and ischemic limb models. Immunophenotypic analysis indicated that hUCMSCs cultured in hUCS had more small and rapidly self-renewing cells than those expanded in FCS. The main cause of greater senescence in FCS-cultured cells was increased generation of reactive oxygen species (ROS). Proteome profiling showed significantly more senescence-associated vimentin in FCS-cultured hUCMSCs than in hUCS-cultured hUCMSCs. In contrast, there was significant upregulation of heat shock protein 27 (Hsp27) in the hUCS-cultured hUCMSCs. By gene targeting, we found that overexpression of Hsp27 may downregulate vimentin expression through inhibition of the nuclear translocation of p65 (NF-κB signaling). Thus, an interaction between Hsp27 and vimentin may modulate the degree of senescence in hUCS- and FCS-cultured hUCMSCs. In summary, hUCMSCs exhibiting senescence are detrimental to cell engraftment and differentiation in animal models via activation of NF-κB pathway. Human stem cells incubated in hUCS might reduce the senescent process through upregulation of Hsp27 to increase implantation efficiency.

Granulocyte colony-stimulating factor activating HIF-1alpha acts synergistically with erythropoietin to promote tissue plasticity.

Stroke and peripheral limb ischemia are serious clinical problems with poor prognosis and limited treatment. The cytokines erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) have been used to induce endogenous cell repair and angiogenesis. Here, we demonstrated that the combination therapy of EPO and G-CSF exerted synergistic effects on cell survival and functional recovery from cerebral and peripheral limbs ischemia. We observed that even under normoxic conditions, G-CSF activates hypoxia-inducible factor-1alpha (HIF-1alpha), which then binds to the EPO promoter and enhances EPO expression. Serum EPO level was significantly increased by G-CSF injection, with the exception of Tg-HIF-1alpha(+f/+f) mice. The neuroplastic mechanisms exerted by EPO combined with G-CSF included enhanced expression of the antiapoptotic protein of Bcl-2, augmented neurotrophic factors synthesis, and promoted neovascularization. Further, the combination therapy significantly increased homing and differentiation of bone marrow stem cells (BMSCs) and intrinsic neural progenitor cells (INPCs) into the ischemic area. In summary, EPO in combination with G-CSF synergistically enhanced angiogenesis and tissue plasticity in ischemic animal models, leading to greater functional recovery than either agent alone.

Induction of GAP-43 modulates neuroplasticity in PBSC (CD34+) implanted-Parkinson's model.

As a result of the progressive decrease in efficacy of drugs used to treat Parkinson's disease (PD) and the rapid development of motor complications, effective alternative treatments for PD are required. In a 6-hydroxydopamine (6-OHDA)-induced Parkinson's rat model, intracerebral peripheral blood stem cell (CD34(+)) (PBSC) transplantation significantly protected dopaminergic neurons from 6-OHDA-induced neurotoxicity, enhanced neural repair of tyrosine hydroxylase neurons through up-regulation of Bcl-2, facilitated stem cell plasticity, and attenuated activation of microglia, in comparison with vehicle-control rats. The 6-OHDA-lesioned hemi-Parkinsonian rats receiving intrastriatal transplantation of PBSCs also showed: 1) enhanced glucose metabolism in the lesioned striatum and thalamus, demonstrated by [(18)F]fluoro-2-deoxyglucose positron emission tomography (FDG-PET), 2) improved neurochemical activity as shown by proton magnetic resonance spectroscopy ((1)H-MRS), and 3) significantly reduced rotational behavior in comparison with control lesioned rats. These observations might be explained by an up-regulation of growth-associated protein 43 (GAP-43) expression because improvements in neurological dysfunction were blocked by injection of MK-801 in the PBSC-treated group. In addition, a significant increase in neurotrophic factor expression was found in the ipsilateral hemisphere of the PBSC-treated group. In summary, this protocol may be a useful strategy for the treatment of clinical PD.

Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke.

Murine olfactory ensheathing cells (OECs) promote central nervous system axonal regeneration in models of spinal cord injury. We investigated whether OECs could induce a neuroplastic effect to improve the neurological dysfunction caused by hypoxic/ischemic stress. In this study, human OECs/olfactory nerve fibroblasts (hOECs/ONFs) specifically secreted trophic factors including stromal cell-derived factor-1alpha (SDF-1alpha). Rats with intracerebral hOEC/ONF implantation showed more improvement on behavioral measures of neurological deficit following stroke than control rats. [18F]fluoro-2-deoxyglucose PET (FDG-PET) showed increased glucose metabolic activity in the hOEC/ONF-treated group compared with controls. In mice, transplanted hOECs/ONFs and endogenous homing stem cells including intrinsic neural progenitor cells and bone marrow stem cells colocalized with specific neural and vascular markers, indicating stem cell fusion. Both hOECs/ONFs and endogenous homing stem cells enhanced neuroplasticity in the rat and mouse ischemic brain. Upregulation of SDF-1alpha and CXCR4 in hOECs/ONFs promoted neurite outgrowth of cocultured primary cortical neurons under oxygen glucose deprivation conditions and in stroke animals through upregulation of cellular prion protein (PrP C) expression. Therefore, the upregulation of SDF-1alpha and the enhancement of CXCR4 and PrP C interaction induced by hOEC/ONF implantation mediated neuroplastic signals in response to hypoxia and ischemia.

Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke.

Secretoneurin (SN), a neuropeptide derived from secretogranin II, promotes neurite outgrowth of immature cerebellar granule cells. SN also aids in the growth and repair of neuronal tissue, although the precise mechanisms underlying the promotion of brain tissue neuroprotection and plasticity by SN are not understood. Here, in a rat model of stroke and in ischemic human brain tissue, SN was markedly upregulated in both neurons and endothelial cells. SN-mediated neuroprotection rescued primary cortical cell cultures from oxygen/glucose deprivation. SN also induced expression of the antiapoptotic proteins Bcl-2 and Bcl-xL through the Jak2/Stat3 pathway and inhibited apoptosis by blocking caspase-3 activation. In addition, rats with occluded right middle cerebral arteries showed less cerebral infarction, improved motor performance, and increased brain metabolic activity following i.v. administration of SN. Furthermore, SN injection enhanced stem cell targeting to the injured brain in mice and promoted the formation of new blood vessels to increase local cortical blood flow in the ischemic hemisphere. Both in vitro and in vivo, SN not only promoted neuroprotection, but also enhanced neurogenesis and angiogenesis. Our results demonstrate that SN acts directly on neurons after hypoxia and ischemic insult to further their survival by activating the Jak2/Stat3 pathway.

Culturing adult human bone marrow stem cells on gelatin scaffold with pNIPAAm as transplanted grafts for skin regeneration.

Skin tissue engineering is a possible solution for the treatment of extensive skin defect. The ultimate goal of skin tissue engineering is to restore the complete functions of native skin, but until now the structures and functions of skins are only partially restored. By negative immunoselection (CD45 and glycophorin A), we isolated and cultivated adult human bone marrow stem cells (hBMSCs) that are of multilineage differentiation potential. In this study, we first demonstrated that by using gelatin/thermo-sensitive poly N-isopropylacrylamide (pNIPAAm) and the immunocompromised mice model, the hBMSCs possess the differentiation potential of epidermis and the capability of healing skin wounds. The in vitro observations and the results of the scanning electron microscope showed that the hBMSCs can attach and proliferate in the gelatin/thermo-sensitive pNIPAAm. To further monitor the in vivo growth effect of the hBMSCs in the skin-defected nude mice, the green fluorescence protein (GFP) gene was transduced into the hBMSCs by the murine stem cell viral vector. The results showed that the rates of cell growth and wound recovery in the hBMSC-treated group were significantly higher than those in the control group, which was only treated with the gelatin/pNIPAAm (p < 0.01). More importantly, the re-epithelialization markers of human pan-cytokeratin and E-cadherin were significantly increased on day 7, day 14, and day 21 after the hBMSC-scaffold with the pNIPAAM in the mice with skin defects (p < 0.05). Moreover, the stem cell markers of human CD13 and CD105 were gradually decreased during the period of wound healing. In sum, this novel method provides a transferring system for cell therapies and maintains its temperature-sensitive property of easy-peeling by lower-temperature treatment. In addition, the in vitro and in vivo GFP imaging systems provide a new imaging modality for understanding the differentiation process and the effective expression of stem cells in wound healing.

Stromal cell-derived factor-1 alpha promotes neuroprotection, angiogenesis, and mobilization/homing of bone marrow-derived cells in stroke rats.

Stromal cell-derived factor (SDF)-1alpha is involved in the trafficking of hematopoietic stem cells from bone marrow to peripheral blood, and its expression is increased in the penumbra of the ischemic brain. In this study, SDF-1alpha was found to exert neuroprotective effects that rescued primary cortical cultures from H(2)O(2) neurotoxicity, and to modulate neurotrophic factor expression. Rats receiving intracerebral administration of SDF-1alpha showed less cerebral infarction due to up-regulation of antiapoptotic proteins, and they had improved motor performance. SDF-1alpha injection enhanced the targeting of bone marrow (BM)-derived cells to the injured brain, as demonstrated in green fluorescent protein-chimeric mice with cerebral ischemia. In addition, increased vascular density in the ischemic cortex of SDF-1alpha-treated rats enhanced functional local cerebral blood flow. In summary, intracerebral administration of SDF-1alpha resulted in neuroprotection against neurotoxic insult, and it induced increased BM-derived cell targeting to the ischemic brain, thereby reducing the volume of cerebral infarction and improving neural plasticity.

Cilostazol attenuates MCP-1 and MMP-9 expression in vivo in LPS-administrated balloon-injured rabbit aorta and in vitro in LPS-treated monocytic THP-1 cells.

Monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) are involved in vascular inflammation. We tested the hypothesis, and explored the underlining mechanisms that cilostazol, a phosphodiesterase 3 inhibitor with antiplatelet and antithrombotic properties, inhibits lipopolysaccharide (LPS)-induced MCP-1 and MMP-9 expression. In a rabbit aorta balloon-injury model, administration of LPS increased macrophage infiltration and MCP-1 and MMP-9 expression; cilostazol supplementation prevented this phenomenon and reduced intimal hyperplasia. In contrast, the reverse zymography showed that cilostazol did not affect TIMP-1 expression in serum. In monocytic THP-1 cells, cilostazol and N6,O2'-dibutyryl-cAMP (dioctanoyl-cAMP, a cAMP analog) dose-dependently inhibited LPS-induced MCP-1 protein expression and MMP-9 activation, but did not affect the tissue inhibitor of metalloproteinase-1. Quantitative real-time polymerase chain reaction (PCR) showed that cilostazol inhibited MCP-1 and MMP-9 mRNA expression. Cilostazol significantly inhibited LPS-induced activation of p38, JNK, and nuclear factor-kappaB, and the respective inhibitors of p38 and JNK greatly reduced the level of LPS-induced MCP-1 and MMP-9, suggesting the involvement of the p38 and JNK pathways. In conclusion, cilostazol administered with LPS in vivo reduced neointimal hyperplasia and macrophage infiltration in the balloon-injured rabbit aorta; in vitro, cilostazol inhibits LPS-induced MCP-1 and MMP-9 expression. These data suggest that cilostazol may play an important role in preventing endotoxin- and injured-mediated vascular inflammation.

New molecular insights into cellular survival and stress responses: neuroprotective role of cellular prion protein (PrPC).

Knowledge of the physiological function of cellular prion protein has been acquired from prion diseases such as Creutzfeldt-Jakob disease, as well as PRNP knock out and transgenic mice. Recent progress in neurobiology has further delineated the neuroprotective role played by cellular prion protein. In this paper, we review the role of cellular prion protein in cell survival including its antiapoptotic effect on Bax-mediated cell death and its responses to various environmental stresses including oxidative stress, and ischemia. Finally, we discuss the significance of cellular prion protein in different neurodegenerative diseases and the possible development of future therapies.

Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model.

Neuroplasticity subsequent to functional angiogenesis is an important goal for cell-based therapy of ischemic neural tissues. At present, the cellular and molecular mechanisms involved are still not well understood. In this study, we isolated mesenchymal stem cells (MSCs) from Wharton's jelly (WJ) to obtain clonally expanded human umbilical cord-derived mesenchymal stem cells (HUCMSCs) with multilineage differentiation potential. Experimental rats receiving intracerebral HUCMSC transplantation showed significantly improved neurological function compared to vehicle-treated control rats. Cortical neuronal activity, as evaluated by proton MR spectroscopy (1H-MRS), also increased considerably in the transplantation group. Transplanted HUCMSCs migrated towards the ischemic boundary zone and differentiated into glial, neuronal, doublecortin+, CXCR4+, and vascular endothelial cells to enhance neuroplasticity in the ischemic brain. In addition, HUCMSC transplantation promoted the formation of new vessels to increase local cortical blood flow in the ischemic hemisphere. Modulation by stem cell-derived macrophage/microglial interactions, and increased beta1-integrin expression, might enhance this angiogenic architecture within the ischemic brain. Inhibition of beta1-integrin expression blocked local angiogenesis and reduced recovery from neurological deficit. In addition, significantly increased modulation of neurotrophic factor expression was also found in the HUCMSC transplantation group. In summary, regulation of beta1-integrin expression plays a critical role in the plasticity of the ischemic brain after the implantation of HUCMSCs.