Engineered allogeneic mesenchymal stem cells repair femoral segmental defect in rats

Abstract

Bone marrow derived mesenchymal stem cells (MSC) have been shown to be progenitor cells for mesenchymal tissues. These cells may also provide a potential therapy for bone repair. Our previous studies showed that MSC engineered with the gene for bone morphogenetic protein 2 (BMP-2), a growth factor for bone cells, were capable of differentiating into osteoblast lineage and inducing autologous bone formation in several animal models. Culturing individual MSC for autologous implantation, however, remains problematic. The number of human MSC with osteogenic potential decreases with age, and, in certain diseases, the patient's marrow may be damaged or the healthy cells reduced in number. In this study, we used rats with a femoral segmental defect to investigate whether allogeneic BMP-2 engineered MSC would facilitate bone healing. We show that BMP-2 engineered allogeneic MSC can repair critical bone defects to the same degree as rats treated with BMP-2 engineered autologous MSC, if the allogeneic group receives short-term treatment with immunosuppressant FK506. We also show that allogeneic gene transferred MSC are directly involved in bone repair, in addition to acting as gene deliverers.

Quantifying Massive Allograft Healing of the Canine Femur In Vivo and Ex Vivo: A Pilot Study

“…As a result, investigators have developed preclinical adjuvant therapies [6,11,12,15,19,24,26,[30][31][32][33]. As yet, their clinical application has been unrealized, largely because a large-animal model has not been established, nor have clinically relevant diagnostic tools that can noninvasively quantify graft healing.…”

“…These limitations, in addition to graft type (intercalary/osteochondral), preservation technique, and internal fixation approach, are associated with a 25% to 35% failure rate due to nonunion and fracture [2,14] and a 10-year survival rate of less than 50% due to the accumulation of unremodeled microfractures, which compromise their mechanical properties [29]. To address these shortcomings, investigators have developed biologic adjuvant therapies (ie, BMP-2 [6,15,32], teriparatide [19,24]), stem cell [26,30,33], and gene [11,12,31]), which stimulate integration of cortical allografts. While these technologies have accelerated healing in small-animal models, their application in humans has been unrealized.…”

Transfer and Stable Transgene Expression of a Mammalian Artificial Chromosome into Bone Marrow‐Derived Human Mesenchymal Stem Cells

“…This list includes the replacement of genes to correct acquired or inherited disorders of bone, muscle, or cartilage by transfer of genes encoding bone morphogenic proteins -2, -4, -9 [21,[32][33][34][35][36][37][38][39][40], the transfer of genes encoding the blood coagulation factors VIII and IX for the treatment of hemophilia [41][42][43][44][45][46][47], human growth hormone [46,48], insulin-like growth factor 1 [49], and interleukin-3 [50]. This list also includes: erythropoietin [51], α-l-iduronidase for treatment of mucopolysaccharidosis type I [52], proα2 collagen (I) for treatment of osteogenesis imperfecta [53], sox9 [54] to enhance chondrogenesis, and interferon to treat tumors [55].…”

Treatment of avascular necrosis of the femoral head by hepatocyte growth factor-transgenic bone marrow stromal stem cells

“…BMSCs are bone progenitor cells with excellent potential for differentiation into osteoblasts 18,19 that can restore bone tissue. 20 BMSCs can be easily isolated from bone and transfected with an exogenous gene.…”