Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases

Abstract

The intriguing biology of stem cells and their vast clinical potential is emerging rapidly for gene therapy. Bone marrow stem cells, including the pluripotent haematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and possibly the multipotent adherent progenitor cells (MAPCs), are being considered as potential targets for cell and gene therapy-based approaches against a variety of different diseases. The MSCs from bone marrow are a promising target population as they are capable of differentiating along multiple lineagesn and, at least in vitro, have significant expansion capability. The apparently high self-renewal potential makes them strong candidates for delivering genes and restoring organ systems function. However, the high proliferative potential of MSCs, now presumed to be self-renewal, may be more apparent than real. Although expanded MSCs have great proliferation and differentiation potential in vitro, there are limitations with the biology of these cells in vivo. So far, expanded MSCs have failed to induce durable therapeutic effects expected from a true self-renewing stem cell population. The loss of in vivo self-renewal may be due to the extensive expansion of MSCs in existing in vitro expansion systems, suggesting that the original stem cell population and/or properties may no longer exist. Rather, the expanded population may indeed be heterogeneous and represents several generations of different types of mesenchymal cell progeny that have retained a limited proliferation potential and responsiveness for terminal differentiation and maturation along mesenchymal and non-mesenchymal lineages. Novel technology that allows MSCs to maintain their stem cell function in vivo is critical for distinguishing the elusive stem cell from its progenitor cell populations. The ultimate dream is to use MSCs in various forms of cellular therapies, as well as genetic tools that can be used to better understand the mechanisms leading to repair and regeneration of damaged or diseased tissues and organs.

Cord lining progenitor cells: potential in vitro adipogenesis model

“…Cells were plated at a density of 5000 cells per cm 2 and cultured at 37 1C in an atmosphere of 95% air and 5% carbon dioxide. Upon reaching confluency at passage 3 or 4, CLMCs were divided into different treatment groups as shown in Table 1.…”

“…1 There has been emerging evidence that these pluripotent cells have promising applications for regenerative medicine and cell therapies. 2,3 Unfortunately, the ethical concerns and controversies surrounding the usage of embryonic stem cells have been a major road block to its research and clinical applications. As such, multipotent mesenchymal progenitor cells are an attractive alternative.…”

Therapeutic potential of genetically modified mesenchymal stem cells

“…[1][2][3] MSC are considered nonhematopoietic multipotent stem-like cells that have selfrenewing potential, capable of differentiating into both mesenchymal and non-mesenchymal lineages. 4,5 In much of the literature, the adherent fibroblastic cells from the bone marrow are termed MSC or mesenchymal progenitor cells; however, this heterogeneous population is recognized, among leading investigators, to be too 'crude' to be considered all MSC and the thinking about these bone marrow-derived cells will likely be redefined over the coming years.…”

“…A typical protocol to obtain MSC from mouse bone marrow is described elsewhere. 4 The addition of FGF2 in MSC cultures helps to maintain the cells in pluripotent and undifferentiated state. Normally, residual macrophages from the MSC culture are removed using anti-mouse CD11b beads.…”

Extended and stable gene expression via nucleofection of MIDGE construct into adult human marrow mesenchymal stromal cells

“…Genetic modifications of MSC with therapeutic genes make them more effective for therapeutic use (Reiser et al 2005). These cells have been manipulated for the delivery of various genes including cytotoxic T lymphocyte antigen-imunoglobulin (CTLA-Ig), factor VIII, interleukin-2 and tumor necrosis factor apoptosis ligand (TRAIL) to treat graft versus host disease (GvHD), hemophilia A, glioma and glioblastoma, respectively (Deng et al 2003;Doering 2008;Nakamura et al 2004;Sasportas et al 2009;Van Damme et al 2003).…”