Repair of Lateral Hemisection Lesion in Spinal Cord Using Schwann Cells Differentiated from Subcutaneous Fat Tissue Delivered in Fibrin Plug

( Guang Fan Chi ),( Mi Ra Kim ),( Dae Wook Kim ),( Mei Hua Jiang ),( Eun Kyung Chung ),( Young Sook Son ) 한국조직공학·재생의학회 2011 조직공학과 재생의학 Vol.8 No.2

Previously, we showed that rat subcutaneous fat tissue comprises of nestin-expressing spheroids, which are efficiently induced to Schwann cells (SCs) in vitro under the inducing condition and display Schwann cell properties in vivo. In this study, we investigated whether induced SCs could be engaged in the repair of the lateral hemisection lesion of the rat spinal cord using PKH26-labeled cells and also tested the feasibility of fibrin glue as a cell delivery vehicle in the blunt gap lesion. At the end of twelve weeks after the transplantation, the lesion site was fully filled with the regenerated tissue, which contained PKH26-labeled cells and P0 expressing cells. Some of PKH26-labeled cells were shown as a hollow tube-like structure, which was co-localized with the P0 antigen. Several types of neurons were also detected in the regenerated tissue. Among them, a few GABAnergic interneuron, CGRP positive neurons, and serotonergic neurons were found at the hemisection lesion site, which were probably infiltrated to the lesion site from the surrounding normal tissue. However, in the control lesion which received fibrin glue only, the majority of lesion site was filled with connective tissue containing numerous fibroblasts and relatively fewer SCs and neurons compared to those in SCs treated group. Thus, the induced SCs delivered with fibrin glue survived at the lesion site in the spinal cord and engaged in the myelin sheath regeneration. Furthermore, SCs along with the fibrin glue, applied as a cell delivery vehicle, seem to provide permissive microenvironment for the active infiltration of host neural and glial cells from the uninjured neighboring tissue.

Substance P reduces apoptotic cell death possibly by modulating the immune response at the early stage after spinal cord injury

Jiang, Mei Hua,Lim, Ji Eun,Chi, Guang Fan,Ahn, Woosung,Zhang, Mingzi,Chung, Eunkyung,Son, Youngsook Wolters Kluwer Health | Lippincott Williams Wilkin 2013 NEUROREPORT - Vol.24 No.15

Previously, we have reported that substance P (SP) enhanced functional recovery from spinal cord injury (SCI) possibly by the anti-inflammatory modulation associated with the induction of M2-type macrophages at the injured lesion. In this study, we explored the cytokine expression profiles and apoptotic cell death in the lesion site of the SCI after an immediate intravenous injection of SP. SP injection increased the levels of interleukin-4 (IL-4), IL-6, and IL-10 at day 1 after the SCI approximately by 2-, 9-, and 10-folds when compared with the control SCI, respectively. On the basis of double immunofluorescence staining with IL-10 and CD11b, activated macrophages or microglia expressing IL-10 appeared in the margin of the lesion site at day 1 only after the SP injection. This SP-mediated alteration in the lesion microenvironment was shown to be associated with the lower cell death of neuronal cells at day 1 and oligodendrocytes at day 5 by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, which was also accompanied by a decrease in caspase-3 activation. These findings suggest that SP may reduce the inflammation-induced secondary cell death, possibly through immune modulation at an early stage after the SCI.

Study on the Relationship Between CXCR4 Expression and Perineural Invasion in Pancreatic Cancer

Jiang, Yu-Mei,Li, Guang,Sun, Bao-Cun,Zhao, Xiu-Lan,Zhou, Zhong-Kai Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.12

Background: Recent reports have shown that C-X-C chemokine receptor 4 (CXCR4) plays an important role in metastasis. Despite a clear understanding of the protein's structure and properties, its functional role remains elusive. We conducted the present study to evaluate the expressions of CXCR4 in pancreatic cancer, and to investigate its relationship with clinicopathological parameters, especially perineural invasion(PNI). Materials and Methods: The association between CXCR4 expression and perineural invasion was determined by immunohistochemistry in pancreatic cancer patients (n=51). Results: CXCR4 expression was correlated with the existence of PNI and the type of PNI (p=0.042, p=0.040). TIMP-2 expression was also correlated with the existence, the pathway and degree of PNI (p=0.000, p=0.006, p=0.000). Conclusions: Our results suggest an association between PNI and expression of CXCR4 and TIMP-2 in pancreatic cancer. CXCR4 may promote the occurrence of PNI in pancreatic cancer cells by decreasing the inhibition of TIMPs on MMP.

Spheroids Derived from Subcutaneous Tissue or Dermis Are Distinct from Neurospheroids Derived from Hippocampus

( Guang Fan Chi ),( Hyeong Won Choi ),( Mei Hua Jiang ),( Dai Wook Kim ),( Eun Kyung Chung ),( Young Sook Son ) 한국조직공학·재생의학회 2011 조직공학과 재생의학 Vol.8 No.2

In this study, we tested whether the subcutaneous tissue and/or dermis retain inherently the spheroid forming cells or those spheroids are induced by the special induction condition and furthermore explored how much distinct or similar to neurospheroid derived from neural stem cells in the hippocampus. Based on immunofluorescence staining, nestin and p75 positive cells were abundant in both skin appendages of subcutaneous tissue and dermal compartment of neonatal rat skin and could generate numerous spheroids upon the incubation with bFGF and EGF containing spheroid inducing medium. Those spheroids were all identical in gene expressions of Twist, Slug, Sox9, Sox2, nestin, p75, and ABCG2. However, spheroids derived from the hippocampus, which were featured by the lack of p75 and fibronectin expression, were quite distinct from those from subcutaneous and dermis tissue. In the spheroid, nestin and p75 were initially expressed only in the central part of the spheroids but later became positive in all cells of the spheroids after two week culture and the cell proliferation was restricted within the spheroid structure. By neural differentiation and Schwann cell differentiation, the spheroid forming cells could be differentiated to β tubulin- III positive neural lineage cell and Sox10, GFAP positive Schwann cells, respectively. Therefore, our findings indicate that the subcutaneous tissue of neonatal rat skin comprised of numerous spheroid forming cells, possibly similar to neural crest derived stem cells and may be an alternative new source of neural and glial cell lineages for peripheral and central nervous system disease or disorders.

Schwann cells differentiated from spheroid-forming cells of rat subcutaneous fat tissue myelinate axons in the spinal cord injury

Chi, Guang Fan,Kim, Mi-ra,Kim, Dae-Wook,Jiang, Mei Hua,Son, Youngsook Elsevier 2010 Experimental neurology Vol.222 No.2

<P><B>Abstract</B></P><P>In the present study, we found that nestin-expressing spheroid cells derived from multipotent adipose stem cells of subcutaneous fat tissue could efficiently differentiate into Schwann cells (SCs) <I>in vitro</I> based on expression of SC markers such as A2B5, GFAP, O4, p75, S100, Sox10, Krox-20, and L1. The induced SC is engrafted to spinal cord injury lesions and formed a peripheral nervous system (PNS)-type myelin sheath on central nervous system (CNS) axons. PNS-type myelin sheath formation in repaired tissue was confirmed by transplantation of both induced PKH26-labeled SC and induced EGFP-expressing SC generated from EGFP transgenic rats. In addition to direct participation as myelin sheath-forming SC in repaired tissue, the induced SC also expressed several neurotrophic factors, as did native SC, which may suggest an additional role for induced SC in stimulation of endogenous healing responses. Thus, spheroid-forming cells from subcutaneous fat tissue demonstrated rapid and efficient induction into SC, and such cells show therapeutic promise for repair of damage to the CNS and PNS.</P>

Schwann-like cells from human melanocytes and their fate in sciatic nerve injury

Chi, Guang Fan,Kim, Dae-wook,Jiang, Mei Hua,Yoon, Kang Jun,Son, Youngsook Lippincott Williams Wilkins, Inc. 2011 NEUROREPORT - Vol.22 No.12

We induced human melanocyte dedifferentiation to Schwann cell-like cells in vitro by a combination of forskolin, neuregulin-&bgr;1, neurotrophin-3, platelet-derived growth factor-aa, basic fibroblast growth factor, laminin, and heparin. Cultured human melanocytes constitutively expressed neural cell and melanocyte markers but melanocyte-specific marker, including microphthalmia-associated transcription factor and tyrosinase, expression was selectively lost after induction. In the sciatic nerve injury site, the induced cells were engrafted and closely aligned to axons and P0-expressing myelin sheaths, whereas uninduced cells were not colocalized with axons and myelin sheaths and reexpressed melanocyte-specific tyrosinase activity in vivo. Human melanocytes lose their melanocyte phenotype and transdifferentiate into Schwann cells under specific induction conditions and display their Schwann cell phenotype after transplantation to injured sciatic nerve tissue.

A novel panel of serum miR-21/miR-155/miR-365 as a potential diagnostic biomarker for breast cancer

Ji-Guang Han,Yong-Dong Jiang,Chun-Hui Zhang,Yan-Mei Yang,Da Pang,Yan-Ni Song,Guo-Qiang Zhang 대한외과학회 2017 Annals of Surgical Treatment and Research(ASRT) Vol.92 No.2

Purpose: Insufficient sensitivity and specificity prevent the use of most existing biomarkers for early detection of breast cancer. Recently, it was reported that serum microRNAs (miRNAs) may be potential biomarkers in many cancer diseases. In this study, we investigated whether serum levels of 5 miRNAs including miR-21, miR-125b, miR-145, miR-155, and miR-365 could discriminate breast cancer patients and healthy controls. Methods: Serum levels of miRNAs were measured by using quantitative real-time polymerase chain reaction in 99 breast cancer patients and 21 healthy controls. The abundance change of serum miRNAs were also evaluated following surgical resection in 20 breast cancer patients. Receiver operating characteristic (ROC) curve analysis was performed to assess the sensitivity and specificity of miRNAs as diagnostic biomarkers. Results: Serum levels of miR-21 and miR-155 was significantly higher, while miR-365 was significantly lower in breast cancer as compared with healthy controls. The serum levels of miR-21 and miR-155 significantly decreased following surgical resection. Additionally, the serum level of miR-155 at stages I and II was significantly higher compared to stage III. The serum miR-145 level was remarkably higher in progesterone receptor (PR)-positive patients than PR-negative. The positivity of miR-21, miR-155, and miR-365 was high compared to CA 153 and CEA in breast cancer. ROC curve analyses of a combination of miR-21, miR-155, and miR-365 yielded much higher area under curve and enhanced sensitivity and specificity in comparison to each miRNA alone. Conclusion: The combination of serum miR-21/miR-155/miR-365 may potentially serve as a sensitive and specific biomarker that enables differentiation of breast cancer from healthy controls.

Continuous DC-CIK Infusions Restore CD8⁺ Cellular Immunity, Physical Activity and Improve Clinical Efficacy in Advanced Cancer Patients Unresponsive to Conventional Treatments

Zhao, Yan-Jie,Jiang, Ni,Song, Qing-Kun,Wu, Jiang-Ping,Song, Yu-Guang,Zhang, Hong-Mei,Chen, Feng,Zhou, Lei,Wang, Xiao-Li,Zhou, Xin-Na,Yang, Hua-Bing,Ren, Jun,Lyerly, Herbert Kim Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.6

Background: There are few choices for treatment of advanced cancer patients who do not respond to or tolerate conventional anti-cancer treatments. Therefore this study aimed to deploy the benefits and clinical efficacy of continuous dendritic cell-cytokine induced killer cell infusions in such patients. Materials and Methods: A total of 381 infusions (from 67 advanced cases recruited) were included in this study. All patients underwent peripheral blood mononuclear cell apheresis for the following cellular therapy and dendritic cells-cytokine induced killer cells were expanded in vitro. Peripheral blood T lymphocyte subsets were quantified through flow cytometry to address the cellular immunity status. Clinical efficacy and physical activities were evaluated by RECIST criteria and Eastern Cooperative Oncology Group scores respectively. Logistic regression model was used to estimate the association between cellular infusions and clinical benefits. Results: An average of $5.7{\pm}2.94{\times}10^9$ induced cells were infused each time and patients were exposed to 6 infusions. Cellular immunity was improved in that cytotoxic $CD8^+CD28^+$ T lymphocytes were increased by 74% and suppressive $CD8^+CD28^-$ T lymphocytes were elevated by 16% (p<0.05). Continuous infusion of dendritic cells-cytokine induced killer cells was associated with improvement of both patient status and cellular immunity. A median of six infusions were capable of reducing risk of progression by 70% (95%CI 0.10-0.91). Every elevation of one ECOG score corresponded to a 3.90-fold higher progression risk (p<0.05) and 1% increase of $CD8^+CD28^-$ T cell proportion reflecting a 5% higher risk of progression (p<0.05). Conclusions: In advanced cancer patients, continuous dendritic cell-cytokine induced killer cell infusions are capable of recovering cellular immunity, improving patient status and quality of life in those who are unresponsive to conventional cancer treatment.

SPON2 Promotes M1-like Macrophage Recruitment and Inhibits Hepatocellular Carcinoma Metastasis by Distinct Integrin–Rho GTPase–Hippo Pathways

Zhang, Yan-Li,Li, Qing,Yang, Xiao-Mei,Fang, Fang,Li, Jun,Wang, Ya-Hui,Yang, Qin,Zhu, Lei,Nie, Hui-Zhen,Zhang, Xue-Li,Feng, Ming-Xuan,Jiang, Shu-Heng,Tian, Guang-Ang,Hu, Li-Peng,Lee, Ho-Young,Lee, Su-J American Association for Cancer Research 2018 Cancer research Vol.78 No.9

<P>Matricellular protein SPON2 acts as an HCC suppressor and utilizes distinct signaling events to perform dual functions in HCC microenvironment.</P><P>Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signaling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-Actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2-α5β1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.</P><P><B>Significance:</B> Matricellular protein SPON2 acts as an HCC suppressor and utilizes distinct signaling events to perform dual functions in HCC microenvironment.</P><P><B>Graphical Abstract:</B> http://cancerres.aacrjournals.org/content/canres/78/9/2305/F1.large.jpg. <I>Cancer Res; 78(9); 2305–17. ©2018 AACR</I>.</P><P><B>Graphical Abstract</B></P><P> [Figure]</P>

Intravenous Tenecteplase for Acute Ischemic Stroke Within 4.5–24 Hours of Onset (ROSE-TNK): A Phase 2, Randomized, Multicenter Study

Wang Lu,Dai Ying-Jie,Cui Yu,Zhang Hong,Jiang Chang-Hao,Duan Ying-Jie,Zhao Yong,Feng Ye-Fang,Geng Shi-Mei,Zhang Zai-Hui,Lu Jiang,Zhang Ping,Zhao Li-Wei,Zhao Hang,Ma Yu-Tong,Song Cheng-Guang,Zhang Yi,Ch 대한뇌졸중학회 2023 Journal of stroke Vol.25 No.3

Background and Purpose Intravenous tenecteplase (TNK) efficacy has not been well demonstrated in acute ischemic stroke (AIS) beyond 4.5 hours after onset. This study aimed to determine the effect of intravenous TNK for AIS within 4.5 to 24 hours of onset. Methods In this pilot trial, eligible AIS patients with diffusion-weighted imaging (DWI)-fluid attenuated inversion recovery (FLAIR) mismatch were randomly allocated to intravenous TNK (0.25 mg/kg) or standard care within 4.5–24 hours of onset. The primary endpoint was excellent functional outcome at 90 days (modified Rankin Scale [mRS] score of 0–1). The primary safety endpoint was symptomatic intracranial hemorrhage (sICH). Results Of the randomly assigned 80 patients, the primary endpoint occurred in 52.5% (21/40) of TNK group and 50.0% (20/40) of control group, with no significant difference (unadjusted odds ratio, 1.11; 95% confidence interval 0.46–2.66; <i>P</i>=0.82). More early neurological improvement occurred in TNK group than in control group (11 vs. 3, <i>P</i>=0.03), but no significant differences were found in other secondary endpoints, such as mRS 0–2 at 90 days, shift analysis of mRS at 90 days, and change in National Institutes of Health Stroke Scale score at 24 hours and 7 days. There were no cases of sICH in this trial; however, asymptomatic intracranial hemorrhage occurred in 3 of the 40 patients (7.5%) in the TNK group. Conclusion This phase 2, randomized, multicenter study suggests that intravenous TNK within 4.5–24 hours of onset may be safe and feasible in AIS patients with a DWI-FLAIR mismatch.