Potential Use Of Mesenchymal Stem Cells Research Articles

Mesenchymal Stem Cells Enhance the Induction of Mixed Chimerism and Tolerance to Rat Hind-Limb Allografts after Bone Marrow Transplantation

Mixed hematopoietic chimerism via bone marrow transplantation has been shown to induce donor specific tolerance to solid organ allografts, but graft versus host disease (GVHD) remains to be a risk. Composite tissue allografts may need a higher percentage of donor chimerism compared with less immunogenic solid organ allografts. In this study, we investigated the potential of mesenchymal stem cells (MSCs) in the induction of stable and high level chimerism and subsequent donor-specific tolerance to composite tissue allograft without the incidence of graft versus host disease (GVHD). Fully mismatched, 4- to 8-wk-old Brown Norway (RT1(n)) and Lewis (RT1(1)) rats were used as cell or hind-limb donors and recipients, respectively. Recipients received a conditioning regimen consisting of antilymphocyte serum, standard immunosuppressive therapy (rapamycin: 0.2 mg/kg/d; days 0 approximately 130) and 3 Gy total body irradiation, followed by an intraportal co-infusion of allogeneic MSCs and bone marrow cells (day 0); then performing hind-limb allotransplants (30 d after BMT); 100 d after hind-limb transplantations, immunosuppressive therapy was stopped and to observe the survival time of the hind-limb allografts. When co-infusion of allogeneic MSCs was administered, 14/15 recipients developed stable and high level chimerism. Subsequently, in the donor specific group, the survival time of hind-limb allografts without RAPA were remarkably prolonged compared with other groups. The results of the histopathological evaluation of skin biopsy and mixed lymphocyte cultures confirmed this operational donor specific tolerance. Without MSCs, only 2/7 of the recipients developed stable chimerism, but GVHD occurred in both of them, and the level of the chimerism was much lower. On the other hand, GVHD was not observed in any of the recipients infused with MSCs (0/15). This study indicates a potential use of MSCs for induction of stable and high level mixed hematopoietic chimerism and subsequent donor specific tolerance in clinical composite tissue allotransplantation.

Mesenchymal Stem Cells in Cancer: Tumor-Associated Fibroblasts and Cell-Based Delivery Vehicles

Recent evidence suggests that mesenchymal stem cells (MSC) selectively home to tumors, where they contribute to the formation of tumor-associated stroma. This effect can be opposed by genetically modifying MSC to produce high levels of anti-cancer agents that blunt tumor growth kinetics and inhibit the growth of tumors in situ. In this review article, we describe the biological properties of MSC within the tumor microenvironment and discuss the potential use of MSC and other bone marrow-derived cell populations as delivery vehicles for antitumor proteins.

Mesenchymal Stem Cells Facilitate the Induction of Mixed Hematopoietic Chimerism and Islet Allograft Tolerance without GVHD in the Rat

Induction of hematopoietic chimerism and subsequent donor-specific immune tolerance via bone marrow transplantation is an ideal approach for islet transplantation to treat type-1 diabetes. We examined the potential of mesenchymal stem cells (MSCs) in the induction of chimerism and islet allograft tolerance without the incidence of graft-versus-host disease (GVHD). Streptozotocin-diabetic rats received a conditioning regimen consisting of antilymphocyte serum and 5 Gy total body irradiation, followed by an intraportal co-infusion of allogeneic MSCs, bone marrow cells (BMCs) and islets. Although all the recipients rejected the islets initially, half of them developed stable mixed chimerism and donor-specific immune tolerance, shown by the engraftment of donor skin and second-set islet transplants and acute rejection of a third-party skin. The engraftment of the primary islet allografts with stable chimerism was achieved by the addition of a 2-week peritransplant administration of 15-deoxyspergualin (DSG). Without MSCs, none of the recipients treated with DSG developed chimerism or reversal of diabetes. GVHD was not observed in any of the recipients infused with MSCs (0/15), whereas it occurred in 4/11 recipients without MSCs. These results indicate a potential use of MSCs for induction of hematopoietic chimerism and subsequent immune tolerance in clinical islet transplantation.

Differentiation of human mesenchymal stem cells and articular chondrocytes: Analysis of chondrogenic potential and expression pattern of differentiation‐related transcription factors

Mesenchymal stem cells (MSCs) are a candidate for replacing chondrocytes in cell-based repair of cartilage lesions. However, it has not been clarified if these cells can acquire the hyaline phenotype, and whether chondrocytes and MSCs show the same expression patterns of critical control genes in development. In order to study this, articular chondrocytes and iliac crest derived MSCs were allowed to differentiate in pellet mass cultures. Gene expression of markers for the cartilage phenotype, helix-loop-helix (HLH) transcription factors, and chondrogenic transcription factors were analyzed by real-time PCR. Matrix production was assayed using biochemical analysis for hydroxyproline, glycosaminoglycans, and immunohistochemistry for collagen types I and II. Significantly decreased expression of collagen type I was accompanied by increased expression of collagen types IIA and IIB during differentiation of chondrocytes, indicating differentiation towards a hyaline phenotype. Chondrogenesis in MSCs on the other hand resulted in up-regulation of collagen types I, IIA, IIB, and X, demonstrating differentiation towards cartilage of a mixed phenotype. Expression of HES1 increased significantly during chondrogenesis in chondrocytes while expression in MSCs was maintained at a low level. The HLH gene HES5 on the other hand was only detected in chondrocytes. Expression of ID1 decreased significantly in chondrocytes while the opposite was seen in MSCs. These findings suggest that chondrocytes and MSCs differentiated and formed different subtypes of cartilage, the hyaline and a mixed cartilage phenotype, respectively. Differentially regulated HLH genes indicated the possibility for HLH proteins in regulating chondrogenic differentiation. This information is important to understand the potential use of MSCs in cartilage repair.

再生医療を支える基本概念

Regenerative medicine has made remarkable progress. This has been supported by the development of tissue engineering that was a combination of medicine and engineering. Tissue engineering applies the principles and methods of engineering, material science, and cell and molecular biology toward the development of viable substitutes which restore, maintain, or improve the function of human tissues.According to the theories of tissue engineering, tissues and organs can be regenerated by manipulating three elements: cells, scaffold and regulation factors. In this field, cells mean stem cells that posses both capabilities of self-renewal and differentiation into various tissue-specific cells. Stem cells are divided into two groups: embryonic stem cells (ES cells) and somatic stem cells. Although ES cells are the best cell-source having the omni potency to generate all tissues, ethical problems and rejections by the immune system remains to be resolved. On the other hand, somatic stem cells are promising cell-sources because they are free of the above problems. Actually, almost all clinical applications of regenerative medicine have been performed using somatic stem cells or progenitor cells. Mesenchymal stem cells (MSCs) belonging to somatic stem cells are defined as pluripotent progenitor cells with the ability to generate bone, cartilage, muscle, tendon, ligament and fat. Moreover, in some kind of conditions, MSCs can be differentiated into other lineages: nerve, epithelium and so on. These properties have generated great interest in the potential use of MSCs to replace damaged tissues. Mesenchymal stem cells could be cultured to expand their numbers, or seeded in/on shaped biomimetic scaffold to generate appropriate tissue constructs, then transplanted to the injured site.A scaffold that sustains cells is necessary to regenerate injured tissues and organs. Owe to the development of biotechnology and polymer chemistry, we can create more desirable biomaterial scaffolds with appropriate mechanical properties that can be modified to incorporate biological activity, such as growth factors and structural adhesive proteins. It is no exaggeration to say that successful regeneration of tissues and organs depends on how to establish an appropriate scaffold in the injured site.Regulation factors also play an important role in tissue regeneration. They can induce angiogenesis, which promotes a sufficient supply of oxygen and nutrients to effectively maintain the biological functions of cells transplanted for organ substitution. Therefore, if we do not understanding and manipulate the complex relationships among cells, scaffolds and regulation factors, we cannot repair and/or regenerate tissues and organs.This article discusses the basic principles of tissue engineering and introduces some of the clinical practices in regenerative medicine.