Migration Of Marrow Mesenchymal Stem Cells Research Articles

Transforming growth factor-β1 in the microenvironment of ischemia reperfusion-injured kidney enhances the chemotaxis of mesenchymal stem cells to stromal cell-derived factor-1 through upregulation of surface chemokine (C-X-C motif) receptor 4

Acute renal failure is one of the most common complications observed in hospitals. Although extensive studies have been carried out to search for therapeutic treatments, no effective cure has been established. In recent years, stem cell therapy for tissue engineering and repair has become a key area of study. Bone marrow mesenchymal stem cells (MSCs) have been demonstrated to exhibit a reparative role in ischemia reperfusion-injured kidney tissue, and the stromal cell-derived factor-1 (SDF-1)/chemokine (C-X-C motif) receptor 4 (CXCR4) axis has been found to play an important role in the migration and homing of MSCs. In the present study, transforming growth factor-β1 (TGF-β1) in the homogenate of the acute ischemia reperfusion-injured renal tissue was found to markedly increase the CXCR4 surface expression of MSCs, which contributes to the migration of MSCs to SDF-1. Neutralization of TGF-β1 inhibited the migration in an antibody concentration-dependent manner, through downregulation of CXCR4 localized to the membrane. These observations suggest a potential mechanism for MSC migration to the kidney which may provide a possible therapeutic target for curing acute renal failure.

Aqp1 Enhances Migration of Bone Marrow Mesenchymal Stem Cells Through Regulation of FAK and β-Catenin

Bone marrow mesenchymal stem cells (MSCs) have the potential to migrate to the site of injury and regulate the repair process. Aquaporin 1 (Aqp1) is a water channel molecule and a regulator of endothelial cell migration. To study the role of Apq1 in MSC migration, we manipulated the expression of the Aqp1 gene in MSCs and explored its effects on MSC migration both in vitro and in vivo. Overexpression of Aqp1 promoted MSC migration, while depletion of Aqp1 impaired MSC migration in vitro. When the green fluorescent protein (GFP) labeled Aqp1 overexpressing MSCs were systemically injected into rats with a femoral fracture, there were significantly more GFP-MSCs found at the fracture gap in the Aqp1-GFP-MSC-treated group compared to the GFP-MSC group. To elucidate the underlying mechanism, we screened several migration-related regulators. The results showed that β-catenin and focal adhesion kinase (FAK) were upregulated in the Aqp1-MSCs and downregulated in the Aqp1-depleted MSCs, while C-X-C chemokine receptor type 4 had no change. Furthermore, β-catenin and FAK were co-immunoprecipitated with Aqp1, and depletion of FAK abolished the Aqp1 effects on MSC migration. This study demonstrates that Aqp1 enhances MSC migration ability mainly through the FAK pathway and partially through the β-catenin pathway. Our finding suggests a novel function of Aqp1 in governing MSC migration, and this may aid MSC therapeutic applications.

Effect of Lumican on the Migration of Human Mesenchymal Stem Cells and Endothelial Progenitor Cells: Involvement of Matrix Metalloproteinase-14

BackgroundIncreasing number of evidence shows that soluble factors and extracellular matrix (ECM) components provide an optimal microenvironment controlling human bone marrow mesenchymal stem cell (MSC) functions. Successful in vivo administration of stem cells lies in their ability to migrate through ECM barriers and to differentiate along tissue-specific lineages, including endothelium. Lumican, a protein of the small leucine-rich proteoglycan (SLRP) family, was shown to impede cell migration and angiogenesis. The aim of the present study was to analyze the role of lumican in the control of MSC migration and transition to functional endothelial progenitor cell (EPC).Methodology/Principal FindingsLumican inhibited tube-like structures formation on Matrigel® by MSC, but not EPC. Since matrix metalloproteinases (MMPs), in particular MMP-14, play an important role in remodelling of ECM and enhancing cell migration, their expression and activity were investigated in the cells grown on different ECM substrata. Lumican down-regulated the MMP-14 expression and activity in MSC, but not in EPC. Lumican inhibited MSC, but not EPC migration and invasion. The inhibition of MSC migration and invasion by lumican was reversed by MMP-14 overexpression.Conclusion/SignificanceAltogether, our results suggest that lumican inhibits MSC tube-like structure formation and migration via mechanisms that involve a decrease of MMP-14 expression and activity.

SDF-1/CXCR4 axis modulates bone marrow mesenchymal stem cell apoptosis, migration and cytokine secretion

Bone marrow mesenchymal stem cells (MSCs) are considered as a promising cell source to treat the acute myocardial infarction. However, over 90% of the stem cells usually die in the first three days of transplantation. Survival potential, migration ability and paracrine capacity have been considered as the most important three factors for cell transplantation in the ischemic cardiac treatment. We hypothesized that stromal-derived factor-1 (SDF-1)/CXCR4 axis plays a critical role in the regulation of these processes. In this study, apoptosis was induced by exposure of MSCs to H(2)O(2) for 2 h. After re-oxygenation, the SDF-1 pretreated MSCs demonstrated a significant increase in survival and proliferation. SDF-1 pretreatment also enhanced the migration and increased the secretion of pro-survival and angiogenic cytokines including basic fibroblast growth factor and vascular endothelial growth factor. Western blot and RT-PCR demonstrated that SDF-1 pretreatment significantly activated the pro-survival Akt and Erk signaling pathways and up-regulated Bcl-2/Bax ratio. These protective effects were partially inhibited by AMD3100, an antagonist of CXCR4.We conclude that the SDF-1/CXCR4 axis is critical for MSC survival, migration and cytokine secretion.

Intravenous transplantation of allogeneic bone marrow mesenchymal stem cells and its directional migration to the necrotic femoral head

In this study, we investigated the feasibility and safety of intravenous transplantation of allogeneic bone marrow mesenchymal stem cells (MSCs) for femoral head repair, and observed the migration and distribution of MSCs in hosts. MSCs were labeled with green fluorescent protein (GFP) in vitro and injected into nude mice via vena caudalis, and the distribution of MSCs was dynamically monitored at 0, 6, 24, 48, 72 and 96 h after transplantation. Two weeks after the establishment of a rabbit model of femoral head necrosis, GFP labeled MSCs were injected into these rabbits via ear vein, immunological rejection and graft versus host disease were observed and necrotic and normal femoral heads, bone marrows, lungs, and livers were harvested at 2, 4 and 6 w after transplantation. The sections of these tissues were observed under fluorescent microscope. More than 70 % MSCs were successfully labeled with GFP at 72 h after labeling. MSCs were uniformly distributed in multiple organs and tissues including brain, lungs, heart, kidneys, intestine and bilateral hip joints of nude mice. In rabbits, at 6 w after intravenous transplantation, GFP labeled MSCs were noted in the lungs, liver, bone marrow and normal and necrotic femoral heads of rabbits, and the number of MSCs in bone marrow was higher than that in the, femoral head, liver and lungs. Furthermore, the number of MSCs peaked at 6 w after transplantation. Moreover, no immunological rejection and graft versus host disease were found after transplantation in rabbits. Our results revealed intravenously implanted MSCs could migrate into the femoral head of hosts, and especially migrate directionally and survive in the necrotic femoral heads. Thus, it is feasible and safe to treat femoral head necrosis by intravenous transplantation of allogeneic MSCs.

E0206 Bone marrow mesenchymal stem cell migration depends in part on Kv21 channel activity

ObjectiveThe present study was designed to examine 1. whether hypoxic preconditioning (HP) increases the migration potential of mesenchymal stem cells (MSC) and 2. the mechanistic basis for this effect.MethodsMSCs derived...

Abstract 1283: Endothelial Nitric Oxide Synthase Promotes Mesenchymal Stem Cell Migration Towards the Ischemic Myocardium

Background: Bone marrow mesenchymal stem cells (MSCs) migrate from bone marrow towards the heart and contribute to cardiac repair post myocardial infarction. However, mechanisms by which MSCs migrate to the ischemic heart remain unclear. The present study investigated the role of endothelial nitric oxide synthase (eNOS) on MSC migration towards the ischemic myocardium and whether stromal cell derived factor-1 (SDF-1) contributes to the eNOS-mediated MSC migration. Methods and Results: MSCs were isolated from wild-type (WT) bone marrow and cultured in vitro for 3 generations. Coronary microvascular endothelial cells were isolated from adult mouse hearts and seeded on inserts for transendothelial migration assay. Neonatal cardiomyocytes were isolated from WT, eNOS −/− and eNOS transgenic (Tg) mice, cultured to subconfluence and subjected to 30 min of anoxia followed by 6 hours of reoxygenation (A/R). The conditioned medium was collected and served as a chemoattractant. MSC migration was significantly decreased in eNOS −/− compared to WT conditioned medium (9.8± 1.8% vs. 14.7±2.3%), but increased in eNOS-Tg conditioned medium (38.0±4.5%, P <0.05). SDF-1 protein secretion was significantly decreased in eNOS −/− but increased in eNOS-Tg conditioned medium. To examine MSC migration in vivo, WT, eNOS −/− or eNOS-Tg mice were subjected to myocardial ischemia for 45 min followed by 24 hrs of reperfusion (I/R). Immediately after reperfusion, GFP + MSCs were administered via a tail vein. GFP + cells in the ischemic region were significantly decreased in eNOS −/− compared to WT hearts (3.4±0.3 vs. 5.6±0.4 cell per mm 2 , P<0.05) but significantly increased in eNOS-Tg compared to WT (10.2±1.6 vs. 5.6±0.4 cell per mm 2 , P<0.05). Furthermore, SDF-1 mRNA and protein expression was increased in eNOS-Tg as compared to WT and eNOS −/− after myocardial I/R. Conclusions: eNOS promotes MSC migration towards the ischemic myocardium. This is likely due to an upregulation of SDF-1.

The surface adhesion molecule CXCR4 stimulates mesenchymal stem cell migration to stromal cell-derived factor-1 in vitro but does not decrease apoptosis under serum deprivation

Bone marrow mesenchymal stem cells (MSCs) can be used for myocardial repair following myocardial infarction. Increased expression of stromal cell-derived factor-1 (SDF-1) by an ischemic myocardium attracts CXCR4+ stem cells toward it. CXCR4, the receptor for SDF-1, is important in the migration, homing, and survival of hematopoietic stem cells. Although low levels of CXCR4 expression were found in minor subpopulations of cultured MSCs, most MSCs do not express CXCR4. To optimize the migration and survival of human MSCs, we expressed the CXCR4 gene in these cells using retroviral transduction. We isolated and cultured MSCs from healthy volunteers and transduced them with a retroviral vector containing either CXCR4 and green fluorescent protein (GFP; CXCR4/GFP vector) or GFP alone (control vector). Flow cytometry confirmed successful transduction and GFP and CXCR4 expression. We used a transwell migration system to study MSC migration to SDF-1. We used Annexin V and propidium iodide stains to assess cell survival before and after the survival challenge. Flow cytometry showed that, on average, 83.4+/-17.7% of transduced MSCs expressed CXCR4. Compared with control MSCs, MSCs transduced with CXCR4 showed significantly more migration toward SDF-1, threefold greater at 3 h and more than fivefold greater at 6 h. Mesenchymal stem cells transduced with CXCR4 showed no significant difference in survival under normal to serum-deprived growth conditions. Mesenchymal stem cells can be efficiently transduced to express CXCR4, and transduced MSCs migrate rapidly toward SDF-1. CXCR4 expression does not render survival advantage to MSCs under serum-deprived conditions.