Mesenchymal Stem Cells Overexpressing C-X-C Chemokine Receptor Type 4 Improve Early Liver Regeneration of Small-for-Size Liver Grafts

Abstract

Mesenchymal stem cell (MSC) therapy can prevent hepatic parenchymal cell loss and promote tissue repair. However, poor MSC engraftment is one of the primary barriers to the effectiveness of cell therapy because culture-expanded MSCs progressively downregulate C-X-C chemokine receptor type 4 (CXCR4) expression and lose their ability to migrate toward a concentration gradient of stromal cell-derived factor 1a (SDF1a). In this study, we investigated whether a CXCR4-MSC infusion could protect hepatocytes and stimulate regeneration in 50% reduced size liver transplantation (RSLT). Rats that underwent 50% RSLT were randomly divided into 3 groups: a phosphate-buffered solution group (PBS), a green fluorescent protein (GFP)-MSC group, and a CXCR4-MSC group. Rats received 1 mL of PBS with or without a resuspension of GFP-MSCs or CXCR4-MSCs. The factors secreted by MSCs, the graft function, the apoptosis and proliferation of hepatocytes, the efficacy of MSC engraftment, and the expression of SDF1a, albumin (Alb), and cytokeratin 18 (CK18) in engrafted GFP-positive MSCs were assessed. A systemic infusion of GFP-MSCs led to a reduction of the release of liver injury biomarkers and apoptosis of hepatocytes; CXCR4 overexpression did not further reduce the liver injury. However, CXCR4 overexpression enhanced MSC engraftment in liver grafts, improved the effect on the proliferation of hepatocytes, and thus provided a significant 1-week survival benefit. SDF1a expression in grafts was elevated after transplanted CXCR4-MSCs were recruited to the remnant liver. However, engrafted MSCs did not express the markers of hepatocytes, including Alb and CK18, in vivo 168 hours after transplantation. CXCR4 overexpression enhanced the mobilization and engraftment of MSCs into small-for-size liver grafts, in which these cells promoted the early regeneration of the remnant liver not by direct differentiation but perhaps by a paracrine mechanism.

CXCR4-overexpressing bone marrow-derived mesenchymal stem cells improve repair of acute kidney injury

“…It was observed in our study that null-BMSCs expressed only small amounts of CXCR4. Transplantation of BMSCs that overexpressed CXCR4 led to significant protection against ovariectomy-induced bone loss (4), augmented myoangiogenesis in infarcted myocardium (3,16,43), and induced early liver regeneration of small-for-size liver grafts (7). These observations suggest that overexpression of CXCR4 contributes to enhanced efficacy of BMSC therapy due to the increased homing ability of BMSCs.…”

“…Regulation of CXCR4 expression is expected to influence the directional homing of infused BMSCs. In addition, the SDF-1/CXCR4 axis is also reported to be required for the paracrine actions of BMSCs (7,23). Regulation of CXCR4 expression is also expected to contribute to the paracrine actions of BMSCs.…”

CXCR4 Receptor Overexpression in Mesenchymal Stem Cells Facilitates Treatment of Acute Lung Injury in Rats

“…Adherent cells were fixed with 4% paraformaldehyde for 15 min at room temperature, stained 10 min with 0.5% crystal violet, and counted. The number of transmembrane cells in 10 different fields under the microscope was averaged (26).…”

Clinical Aspects of Regenerative Medicine

“…Other studies emphasizing MSC-assisted regenerative effects were reported in the treatment of the remnant liver [91] and the small-size liver graft [92], which serves as a significant challenge in patients receiving living-related liver transplants. In animal studies, CXCR4 overexpression of MSCs prolonged MSC engraftment, and this finding was associated with significant increased hepatocyte proliferation and improvement of the survival time of liver.…”