Engineered human mesenchymal stem cells: a novel platform for skeletal cell mediated gene therapy

Abstract

hMSCs represent a novel platform for skeletal gene therapy and the present results suggest that they can be genetically engineered to express desired therapeutic proteins inducing specific differentiation pathways. Moreover, hMSCs obtained from osteoporotic patients can restore their osteogenic activity following human BMP-2 gene transduction, an important finding in the future planning of gene therapy treatment for osteoporosis.

Osteoinduction by ex vivo adenovirus-mediated BMP2 delivery is independent of cell type

“…Musgrave et al 10 demonstrated a diverse response in a heterotopic bone formation model, depending on the cell type used for Ad5-BMP2 transduction and intramuscular implantation. Osteogenic cells that were either genetically engineered 8 or transduced 9,18 to express BMP2 have been shown to induce orthotopic bone formation. However, in these studies the cells were delivered using a carrier.…”

“…4,8,9,18 In our study, cells were injected without carrier or scaffold, whereas in all other studies collagen carriers were utilized. 4,8,9,18 Presumably, the carrier immobilizes the cells, decreasing their clearance rate.…”

Functional implication of BMP4 expression on angiogenesis in malignant melanoma

“…Today, more than 30 members of the BMP superfamily have been identified in various tissues and species, and it is known that they control a broad range of biological activities in many cell types like epithelial, mesenchymal or neuronal cells (Mehler et al, 1997;Turgeman et al, 2001). BMPs affect cellular processes like proliferation, differentiation, chemotaxis, motility or cell death (Hogan, 1996).…”

Genetically Engineered Mesenchymal Stem Cells: The Ongoing Research for Bone Tissue Engineering

“…BMP-2, approved by Food and Drug Administration (FDA) for clinical practice, is the most potent member in promoting bone and cartilage development and therefore wins a popular choice for MSCs-based BTE (Lieberman et al, 1998;Lieberman et al, 1999;Lou et al, 1999;Turgeman et al, 2001;Olmsted-Davis et al, 2002;Blum et al, 2003;Gugala et al, 2003;Park et al, 2003;Riew et al, 2003;Tsuda et al, 2003;Kumar et al, 2004;Hasharoni et al, 2005;Egermann et al, 2006;Feeley et al, 2006). The BMP-2-modified MSCs are proven to increase the alkaline phosphatase (ALP) activity, mineralization, and cell proliferation in vitro and induce ectopic bone formation, heal critical size bone defect, repair fracture, and trigger spinal fusion in vivo (Lou et al, 1999;Moutsatsos et al, 2001;Turgeman et al, 2001;Blum et al, 2003;Park et al, 2003;Riew et al, 2003;Tsuda et al, 2003;Hasharoni et al, 2005;Egermann et al, 2006;Feeley et al, 2006). BMP-7 plays a key role in osteoblast differentiation, and there is only one study in which MSCs are engineered with BMP-7.…”

“…An optimal scaffold should provide genetically modified MSCs with the appropriate environment for attachment, proliferation, and differentiation, preventing them from migrating into other places of the body. The scaffold may be soluble for direct injection or solid for surgical implantation (Peng et al, 2001;Turgeman et al, 2001;Blum et al, 2003;Park et al, 2003;Rose et al, 2003;Tsuda et al, 2003;Feeley et al, 2006). Genetically engineered MSCs have the ability to induce bone regeneration not only through paracrine secretion of growth factors to adjacent cells but also by an autocrine effect on MSCs themselves to promote their osteogenic differentiation (Gazit et al, 1999).…”