The potential of stem cells in orthopaedic ability of a single cell, usually a stem cell, to
surgery divide and produce all the differentiated cells in
E H Lee, J H P Hui. Journal of Bone & Joint Surgery. (British an organism volume). London: Jul 2006.Vol.88, Iss. 7; pg. 841, 11 pgs Embryonic stem cells (ESCs) Pluripotent Stem cell therapy holds great promise for the repair & capable of differentiating into many tissue types, regeneration of musculoskeletal tissues Adult stem cells challenges need to be overcome Differentiate to the tissue in which they reside generate adequate numbers of the correct hepatocytes – liver phenotypes of cells under animal-free culture. haemopoietic stem cells - blood appropriate three-dimensional structure under appropriate conditions some can production of extracellular matrix differentiate into multilineages, becoming structurally & biomechanically compliant with the multipotent. demands of native tissue mesenchymal stem cells (MSCs) fully integrated & immunologically compatible, found in bone marrow, skin, adipose with the host tissue tissue, capable of differentiating into bone, cartilage, tendon, ligament, fat Definitions multipotent adult progenitor cell (MAPC)3 Stem cells more pluripotent stem cell Able to self-renew giving rise to more stem cells bone marrow ability to differentiate into tissues of various Transdifferentiation lineages under appropriate conditions cells from one lineage dedifferentiate Pluripotent: giving rise to an intermediate cell type, before Embryonic stem cells (ESCs) redifferentiating into cells of another lineage. able to differentiate into most cell types heart, liver & brain Multipotent can give rise to several other cell types, but Derivation of ESCs those types are limited in number pluripotent ESC Totipotent fertilised oocyte, zygote & morula embryo inner cell mass (ICM) main source of ESC 5-6 day old human blastocyst two distinct cell layers found post-natally in the nonhaemopoietic hypoblast bone marrow stroma, yolk sac also be derived from periosteum, fat & skin. epiblast multipotent cells capable of differentiating differentiates three layers, into cartilage, bone, muscle, tendon, ectoderm, mesoderm & ligament & fat endoderm. great potential repair & regeneration of bone & cartilage. appropriate growth factors & scaffold technology ? possible to repair large defects in bone & cartilage biologically progenitor cells, injected directly into tissues to enhance the process of repair using them as a vehicle for gene delivery.
Mesenchymal stem cells
multipotent progenitor cells capable of differentiating into several connective tissue cell types, including osteocytes, chondrocytes, adipocytes, tenocytes & myocytes characterised by cell surface markers MSCs from bone marrow share the following features. No expression of HSC markers, such as CD34 & CD14. Expression of matrix receptors such as CD44, CD29 & CD71. Expression of MSC markers, SH2 (CD105) & SH3 (CD71).12 Extracellular matrix components: collagen, proteoglycans & fibronectin. Growth factors & cytokine receptors for TGF-β Cell lineages from the Inner Cell Mass (ICM) of human group. blastocysts. TE, trophectoderm; hESC, human embryonic stem cell; GI, gastrointestinal. Articular cartilage Articular cartilage autologous chondrocyte implantation (ACI). Differentiation of human stem cells Chondrocytes stem cells Controlled differentiation periosteum containing stem cells, growth factors chondrocyte precursors direct contact with companion cells Bone specific gene construct transfected into ESCs bone marrow osteoprogenitors autologous human stromal progenitors in Overcoming problems with ESCs the regeneration of large bone defects significant hurdles: cell-based therapy from hESCs. requirements forming a more stable progenitor stage to avoid the osteoproduction, formation of teratomas osteoinduction, ideal serum & xeno-free feeder cell culture media osteoconduction mechanical stimulation. Adult stem cells Osteoproduction more limited in their ability to differentiate into many ability of the cell to secrete bone material. tissue types muscle-derived stem cells present fewer ethical problems Osteoinduction autologous cells: no problems with immunogenicity. growth factors that attract osteogenic cells problem of control of differentiation to the site of the defect propensity to form teratomas is much slighter. TGF-β, bone morphogenetic proteins haemopoietic stem cells (HSCs) & MSCs. (BMPs), BMP-2 & BMP-7, HSCs Osteoconduction already in use clinically incorporation of a structure bearing bone leukaemia, thalassaemia & multiple cells into a recipient site. myeloma Scaffold MSCs BMP regulates chemotaxis, mitosis & differentiation, fundamental in initiating fracture repair Intervertebral disc TGF-β & IGF discogenic back pain stimulate fracture repair & minimise the rate of transplantation to the intervertebral disc of nonunion. mature autologous disc cells, chondrocytes or Requirements stem cells. dose must be of sufficient concentration for a Cell transplantation can potentially increase sustained period proteoglycan production, induce disc short biological half-lives regeneration or slow the process of must be maintained at therapeutic degeneration. concentrations at the fracture site to be effective. transplantation of autologous disc cells & ? role of Gene therapy to solve this chondrocytes derived from costal cartilage Gene therapy MSCs can maintain viability & proliferate within ex vivo the intervertebral disc of the rat. gene encoding for a given growth factor is introduction of appropriate genes into disc cells isolated & transferred to a recipient cell by gene transduction using adenoviral vectors or using viral or non-viral vectors. 'gene-gun' delivery systems genetically modified cells both secrete the Spinal fusion. BMP protein & respond to it, thereby hybrid graft by combining cultured MSCs with a potentially magnifying the clinial response ceramic scaffold muscle-derived stem cells Spinal cord injuries capable of producing sufficient levels of pluripotential cells to differentiate into neural osteoinductive proteins, such as BMP-2, tissue. after transduction with viral vectors. repair of the spinal cord is very complex ? can heal critically sized bony defects restoring or enhancing local spinal reflex no clinical trials of gene therapy for arcs tissue repair. reconnecting regenerating axons from Tendons & ligaments above. MSCs in rabbit Gliosis may block the outgrowth of axons. Repair MSCs isolated in culture from the larger cross-sectional area mononuclear layer of bone marrow can collagen fibres better aligned remyelinate demyelinatecl spinal cord axons higher maximum stresses & moduli at after direct injection into the lesion. 12 & 26 Future strategies for repair of the human spinal ACL cord normal anatomy of the insertion site of the ACL multifaceted, is fibrocartilaginous enhancement of axonal growth & four distinct zones: reconnection, ligament substance, replacement of cellular elements unmineralised fibrocartilage, reversal of demyelination mineralised fibrocartilage Physeal injuries bone cultured chondrocytes have been transferred improve tendon-to-bone healing into physeal defects for the correction of BMP-2 can augment tendon healing in a established growth arrest in animal models bone tunnel Rat: transplantation of autologous chondrocytes rat model that tendons treated with BMP-12 cultured in atelocollagen gel reduced the form a fibrocartilaginous insertion after four angular deformity & length discrepancy of the weeks leg with the injured physis Rabbit Rabbit: implantation of MSCs into growth-plate tendon-bone junction results in a zone defects resulted in a significant reduction in of fibrocartilage at the junction which growth arrest more closely resembled that of the ? donor MSCs differentiated into chondrocytes normal ACL. as well as the host bone marrow cells from the improved biomechanical properties metaphyseal subchondral region, thereby rapid & significant increase in load to generating the repair of the physis. failure & stiffness in the first eight weeks Muscular dystrophy after reconstruction of the ACL a heterogeneous group of neuromuscular Meniscus disorders that produce progressive muscle isolated chondrocytes seeded on to meniscal weakness, muscle wasting matrices were able to bond separate pieces Duchenne muscular dystrophy (DMD), together. in vitro bone marrow differentiates into strength of the adhesion increased over time by contractile myotubes. the formation of a newly synthesised myoblasts could be transplanted into dystrophic cartilaginous matrix. muscle & repaired a small proportion of meniscal lesion involving the inner, avascular, damaged myofibres. one-third of the meniscus benefitted from the delivery of dystrophin by in vivo gene transfer bonding capabilities of the transplant. using viral vectors Osteogenesis imperfecta Pre-clinical studies whole bone marrow contains cells that can engraft & become competent osteoblasts after transplantation. because collagen is a secreted product, even a low level of osteoblast engraftment might be beneficial to patients with OI allogenic bone marrow transplantation in patients with OI 2% of the osteoblasts were of donor origin, suggesting that donor-derived MSC precursors in the marrow were capable of homing to the bone marrow & of differentiation into osteoblasts, or that residual osteoblasts in the bone marrow graft were able to establish in the bone marrow.88 genetic engineering of the individual's own bone marrow with ex vivo genetic modification, Juvenile rheumatoid arthritis autologous stem cell transplantation (ASCT). high-dose therapy supported by autologous stem cell transplantation may induce a good response in such disease Immune ablation followed by reconstitution of autologous haemopoiesis might allow 'resetting' of the immune system through the induction of peripheral tolerance. harvesting the patient's own HSCs aggressive treatment with irradiation &/or high-dose chemotherapy to destroy the cells that are responsible for the inflammatory disease patient's stem cells are then subjected to cycles of T-cell depletion before being infused back into the patient T cells are removed because of their potential to reintroduce the autoreactive state. the use of ASCT for the treatment of human autoimmune disorders, including various rheumatic diseases, is in its infancy.