Review: Gene- and Stem Cell–Based Therapeutics for Bone Regeneration and Repair

Abstract

Many clinical conditions require regeneration or implantation of bone. This is one focus shared by neurosurgery and orthopedics. Current therapeutic options (bone grafting and protein-based therapy) do not provide satisfying solutions to the problem of massive bone defects. In the past few years, gene- and stem cell-based therapy has been extensively studied to achieve a viable alternative to current solutions offered by modern medicine for bone-loss repair. The use of adult stem cells for bone regeneration has gained much focus. This unique population of multipotential cells has been isolated from various sources, including bone marrow, adipose, and muscle tissues. Genetic engineering of adult stem cells with potent osteogenic genes has led to fracture repair and rapid bone formation in vivo. It is hypothesized that these genetically modified cells exert both an autocrine and a paracrine effects on host stem cells, leading to an enhanced osteogenic effect. The use of direct gene delivery has also shown much promise for in vivo bone repair. Several viral and nonviral methods have been used to achieve substantial bone tissue formation in various sites in animal models. To advance these platforms to the clinical setting, it will be mandatory to overcome specific hurdles, such as control over transgene expression, viral vector toxicity, and prolonged culture periods of therapeutic stem cells. This review covers a prospect of cell and gene therapy for bone repair as well as some very recent advancements in stem cell isolation, genetic engineering, and exogenous control of transgene expression.

Bone tissue engineering: A review in bone biomimetics and drug delivery strategies

“…A systematic review of gene therapy in bone regeneration can be found in the literature and is not provided here. 40 Bioreactor systems of a variety of designs have also been utilized to enhance the in vitro performance of osteogenic cells before implantation. Bioreactors simulate the 3D dynamic and mechanical in vivo environment and are designed to provide cells seeded deep within a scaffold with all necessary nutrients and biological cues to survive, proliferate, differentiate, and produce ECM.…”

Technologies Applied to Stimulate Bone Regeneration

“…During the normal regeneration of a fracture, as seen previously, undifferentiated MSCs, with the assistance of BMPs and regulatory cytokines, proliferate and differentiate into chondrocytes and osteoblasts, which will form bone tissue reconstituting the lesion. Although related to the site where they occur, around 5 to 20% or more of fractures present failure in regeneration and consolidation (Kimelman et al, 2007;Undale, et al, 2009). Experiments on animal models using autologous MSCs and different scaffolds have resulted in bone regeneration (Arinzeh et al, 2003;Bruder et al 1998a, b;Kon et al, 2000;Petite et al, 2000).…”

“…These strategies involve both the use of viral and non-viral vectors, presenting genes that code different BMPs, as well as genetically modified cells containing these implanted transgenes. The advance of these studies may be essential for the future prospects of clinical use of stem cells for bone regeneration (Kimelman et al, 2007), bringing more efficient solutions in the field of orthopedics.…”

Osteogenic potency of stem cell-based genetic engineering targeting Wnt3a and Wnt9a

“…Recently, genetic engineering technology has been implicated in stem cell-based bone engineering. During this process, geneticallymodified stem cells are used to produce a sustained increase in osteogenic cytokines and growth factors [3], thus subsequently stimulating osteoblast differentiation of the implanted stem cells and the recipient stem cells [3,4]. For example, overexpression of bone morphogenetic protein-2 (BMP-2) in mesenchymal stem cells has been reported to increase new bone formation in bone defects [4].…”

“…For example, overexpression of bone morphogenetic protein-2 (BMP-2) in mesenchymal stem cells has been reported to increase new bone formation in bone defects [4]. In addition, genetic engineering of a number of other growth factor genes, such as BMP-4 and -7 [3], and of transcription factors, such as runt-related transcription factor 2 (Runx2) and osterix (Osx) [5][6][7][8], have also been shown to induce osteoblast differentiation of progenitor cells.…”