Modifying MSC Phenotype to Facilitate Bone Healing: Biological Approaches

Abstract

Healing of fractures and bone defects normally follows an orderly series of events including formation of a hematoma and an initial stage of inflammation, development of soft callus, formation of hard callus, and finally the stage of bone remodeling. In cases of severe musculoskeletal injury due to trauma, infection, irradiation and other adverse stimuli, deficient healing may lead to delayed or non-union; this results in a residual bone defect with instability, pain and loss of function. Modern methods of mechanical stabilization and autologous bone grafting are often successful in achieving fracture union and healing of bone defects; however, in some cases, this treatment is unsuccessful because of inadequate biological factors. Specifically, the systemic and local microenvironment may not be conducive to bone healing because of a loss of the progenitor cell population for bone and vascular lineage cells. Autologous bone grafting can provide the necessary scaffold, progenitor and differentiated lineage cells, and biological cues for bone reconstruction, however, autologous bone graft may be limited in quantity or quality. These unfavorable circumstances are magnified in systemic conditions with chronic inflammation, including obesity, diabetes, chronic renal disease, aging and others. Recently, strategies have been devised to both mitigate the necessity for, and complications from, open procedures for harvesting of autologous bone by using minimally invasive aspiration techniques and concentration of iliac crest bone cells, followed by local injection into the defect site. More elaborate strategies (not yet approved by the U.S. Food and Drug Administration-FDA) include isolation and expansion of subpopulations of the harvested cells, preconditioning of these cells or inserting specific genes to modulate or facilitate bone healing. We review the literature pertinent to the subject of modifying autologous harvested cells including MSCs to facilitate bone healing. Although many of these techniques and technologies are still in the preclinical stage and not yet approved for use in humans by the FDA, novel approaches to accelerate bone healing by modifying cells has great potential to mitigate the physical, economic and social burden of non-healing fractures and bone defects.

Phosphorylation inhibition of protein-tyrosine phosphatase 1B tyrosine-152 induces bone regeneration coupled with angiogenesis for bone tissue engineering

“…Although great progress has been made in research on the use of bioactive scaffolds for bone regeneration in recent years [ 39 ], MSCs and ECs are still considered to be critical for initiating bone healing [ 40 ]. In fact, evidence for the efficacy of MSCs in promoting bone regeneration comes not only from the ability of MSCs to reverse skeletal metabolic diseases but also from the successful application of MSCs in bone tissue engineering and cell therapy [ 41 , 42 ]. However, although MSC-mediated bone repair has shown great promise, it is still difficult to recruit MSCs to the bone defect site.…”

<p>Inflammation, Bone Healing and Osteonecrosis: From Bedside to Bench</p>

“…Chronic inflammation is a persistent injurious state in which acute inflammation and fibrosis continue, despite ongoing unsuccessful attempts at definitive resolution and repair. 1,9,10 In simple terms, innate immune processes (and if applicable the more restricted antigen-specific adaptive immune system) cannot overcome the offending adverse stimulus to reconstitute normal anatomy and physiology. 11,12 Thus, homeostasis is never achieved despite the continued mobilization of all biological resources.…”

“…91 A recent publication from the present authors summarizes significant modifications to the phenotype of MSCs (more than minimal manipulation) to facilitate bone healing. 9 Some of these techniques include preconditioning with biologics, exposure of MSCs to low oxygen environments, and gene therapy/genetic manipulation of cells. Some other approaches include optimizing techniques for isolation, expansion, and storage of MSCs, and improving the submit your manuscript | www.dovepress.com…”

“…Gene therapy and the genetic manipulation of cells for the purpose of musculoskeletal tissue healing are an exciting concept and have been reviewed elsewhere. 9,92 Gene therapy may be accomplished using chemical and physical methodologies without viruses to transport DNA or microparticles into cells; by the use of gene activated matrices (GAMs) or other platforms that support the release of genetic material to the surrounding cells according to predetermined temporal and spatial parameters; via the use of viral vectors to engineer autologous or allogeneic cells ex vivo with subsequent injection of these cells in vivo; or by direct transfer of genes into cells in vivo. 9 Gene therapy has also been used as a treatment for osteonecrosis, mostly in preclinical studies.…”

“…9,92 Gene therapy may be accomplished using chemical and physical methodologies without viruses to transport DNA or microparticles into cells; by the use of gene activated matrices (GAMs) or other platforms that support the release of genetic material to the surrounding cells according to predetermined temporal and spatial parameters; via the use of viral vectors to engineer autologous or allogeneic cells ex vivo with subsequent injection of these cells in vivo; or by direct transfer of genes into cells in vivo. 9 Gene therapy has also been used as a treatment for osteonecrosis, mostly in preclinical studies. [93][94][95][96][97][98][99][100] We have used BMAC, MSCs, preconditioned MSCs, and genetically modified MSCs that overexpress IL-4 injected into the CD tract with/without a novel 3D printed, customized functionally graded scaffold as a treatment for ONFH in rabbits.…”