Genetically Modified Mesenchymal Stem Cells Induce Mechanically Stable Posterior Spine Fusion

Abstract

Most spine fusion procedures involve the use of prosthetic fixation devices combined with autologous bone grafts rather than biological treatment. We had shown that spine fusion could be achieved by injection of bone morphogenetic protein-2 (BMP-2)-expressing mesenchymal stem cells (MSCs) into the paraspinal muscle. In this study, we hypothesized that posterior spinal fusion achieved using genetically modified MSCs would be mechanically comparable to that realized using a mechanical fixation. BMP-2-expressing MSCs were injected bilaterally into paravertebral muscles of the mouse lumbar spine. In one control group BMP-2 expression was inhibited. Microcomputed tomography and histological analyses were used to evaluate bone formation. For comparison, a group of mouse spines were bilaterally fused with stainless steel pins. The harvested spines were later tested using a custom four-point bending apparatus and structural bending stiffness was estimated. To assess the degree to which MSC vertebral fusion was targeted and to quantify the effects of fusion on adjacent spinal segments, images of the loaded spine curvature were analyzed to extract rigidity of the individual spinal segments. Bone bridging of the targeted vertebrae was observed in the BMP-2-expressing MSC group, whereas no bone formation was noted in any control group. The biomechanical tests showed that MSC-mediated spinal fusion was as effective as stainless steel pin-based fusion and significantly more rigid than the control groups. Local analysis showed that the distribution of stiffness in the MSC-based fusion group was similar to that in the steel pin fusion group, with the majority of spinal stiffness contributed by the targeted fusion at L3-L5. Our findings demonstrate that MSC-induced spinal fusion can convey biomechanical rigidity to a targeted segment that is comparable to that achieved using an instrumental fixation.

Human Adipose Tissue-Derived Stromal Cell Therapy Prevents Bone Loss in Ovariectomized Nude Mouse

“…Most of the studies showing skeletal advantages with MSC therapy were performed by using local injection method in models of fracture healing, 28 calvarial defect, 29 or spinal fusion. 30 In our previous study, we found that systemically administrated murine BMMSC could effectively prevent bone loss after OVX, 18 and here we validated that xenotransplantation of human ADSC could similarly protect against OVX-induced bone mass attenuation, suggesting that systemic therapy of MSCs might have therapeutic potential. In this study we used T cell deficient mice to avoid immune response against human cell transplantation.…”

An injectable method for noninvasive spine fusion

“…Our system is the first approach reported in the literature to achieve clinically relevant spinal fusion in an animal model within 2 weeks through a single intramuscular injection. Although it can be argued that several other systems achieve this goal in various animal models [25–28], each of these studies fall short of a clinically relevant regimen. In a study by Hasharoni et al [25], the authors inject recombinant human BMP2–producing mesenchymal stem cells (MSCs) into the paraspinous muscles of immune-deficient mice.…”

An allograft generated from adult stem cells and their secreted products efficiently fuses vertebrae in immunocompromised athymic rats and inhibits local immune responses

“…Indeed, the majority of the literature strongly supports the need for preconditioning or enhancement of osteogenic capability to dismiss the requirement for excessive cell doses. To this end, genetic modification of osteoprogenitor cells to allow the cells to produce bioactive molecules such as BMP2 [71,76,77] or vascular endothelial growth factor [71] has been performed with some success. However, as with any form of genetic modification, there are serious safety concerns.…”