Stem Cells, Genes, and Tissue
Engineering: Restoring Aging Bones Osteoporosis is currently defined as a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture (94). Clinically, osteoporosis is recognized by the occurrence of characteristic lowtrauma fractures, which typically arise at the hip, spine, and distal forearm. It is estimated that around 40% of US white women and 13% of US white men of 50 yr of age will experience at least one clinically apparent fragility fracture at these sites during their lifetimes (95). However, taking into account sites other than the hip, spine, and distal forearm, the lifetime risk among women aged 50 yr might be as high as 70% (96). The medical costs of osteoporosis and its attendant fractures have been estimated in the US to be $ (17.9 × 109)/yr, with hip fractures accounting for one-third of this total. In England and Wales, hip-fracture patients alone take up 20% of orthopedic beds, with an estimated cost for all osteoporotic fractures of £ (1 × 109)/yr (97). Furthermore, the overall burden on the public health is set to increase dramatically over the next 60 yr because of the steep predicted increase in the proportion of elderly people in the population. Thus, worldwide, there were an estimated 1.66 × 106 hip fractures in 1990, a figure which is predicted to increase to 6.26 × 106 in 2050 if adequate preventative measures are not taken (96). Around 30–50% of the hip operations will require subsequent revision surgery and, in a significant proportion, bone augmentation will be necessary. With an increasing ageing population, overall health costs are set to rise. In addition, the observation that artificial prostheses, which are subjected to wear owing to lack of integration resulting in aseptic loosening, ultimately fail (reviewed in ref. 98), has further driven research activity to exploit the potential of MSCs in bone repair and regeneration (13,16,99). At present, regimes that encourage bone formation or delivery strategies for osteotropic agents such as the BMPs, which hold the promise of significantly increasing bone density, have proved elusive. Tissue engineering seeks to resolve these issues through a combination of stem or progenitor cells with appropriate growth factors and tailored three-dimensional scaffolds. Thus tissue engineering has been defined as the application of scientific principles to the design, construction, modification, and growth of living tissues (100). As a source of progenitor cells, it has long been known that bone has a vast capacity for regeneration from cells with stem cell characteristics. Kadiyala and co-workers have shown that culture-expanded bone marrow cells will heal a segmental bone defect following reimplantation (101).
Several groups have shown that MSCs and osteoprogenitor populations from a variety of species, including human MSCs, do give rise to osteogenic tissue within diffusion chambers (102–104). As detailed above, human bone marrow osteoprogenitors can be isolated and enriched using selective markers, such as STRO-1, from a CD34+ fraction (105,106) and readily expanded, indicating their potential for marrow repopulation (16,26,107,108).Adesirable extension in the use of MSCs for tissue regeneration would be the potential for the use of allogeneic populations allowing the deployment of cells from one or more donors, their preparation, and cryopreservation until required. Studies by Bartholomew et al. (109) and Di Nicola et al. (110) suggest that MSCs may be immune-privileged cells failing to elicit an immune response when combined with allogeneic lymphocytic cells. In support of such an approach, Arinzeh and coworkers (111) have shown that, at least at 4 and 8 wk, allogeneic MSCs aid regeneration in a critical-sized canine segmental defect. No systemic alloantibody production was detected over time (although a few allogeneic cells could be detected at 8 wk); these results add further support to the potential of allogeneic MSCs in cartilage and bone repair. Clinical data from Horwitz and colleagues (112,113) using human bone marrow-derived osteoprogenitors transplanted into children with osteogenesis imperfecta suggest some therapeutic effect of such an approach. Donor-derived MSCs (approx 2%) were capable of homing to the bone marrow and differentiating into the osteoblasts. In follow-up studies, the same group reported an increase in bone mineral content compared with age-matched controls, although the precise contribution of the donor cells to the clinical improvements recorded remains to be determined (114). Connolly (115) as well as Quarto and co-workers (116) have indicated the efficacy of autologous bone marrow stromal cells in the treatment of large bone defects. However, true engraftment of human MSCs, long-term biological effects on the stem cells at the implant site, as well as issues of cell plasticity remains to be defined.