Mesenchymal chondroprogenitor cell origin and therapeutic potential

Review Open Access Mesenchymal chondroprogenitor cell origin and therapeutic potential Janice O'Sullivan†1, Sinéad D'Arcy†1, Frank P Barry1, JMary Murphy1Email author and Cynthia M Coleman1 †Contributed equally Stem Cell Research & Therapy20112:8 https://doi.org/10.1186/scrt49 ©  BioMed Central Ltd 2011 Published: 18 February 2011 Abstract Mesenchymal progenitor cells, a multipotent adult stem cell population, have the ability to differentiate into cells of connective tissue lineages, including fat, cartilage, bone and muscle, and therefore generate a great deal of interest for their potential use in regenerative medicine. During development, endochondral bone is formed from a template of cartilage that transforms into bone; however, mature articular cartilage remains in the articulating joints, where its principal role is reducing friction and dispersing mechanical load. Articular cartilage is prone to damage from sports injuries or ageing, which regularly progresses to more serious joint disorders, such as osteoarthritis. Osteoarthritis is a degenerative joint disease characterized by the thinning and eventual wearing of articular cartilage, and affects millions of people worldwide. Due to low chondrocyte motility and proliferative rates, and complicated by the absence of blood vessels, cartilage has a limited ability to self-repair. Current pharmaceutical and surgical interventions fail to generate repair tissue with the mechanical and cellular properties of native host cartilage. The long-term success of cartilage repair will therefore depend on regenerative methodologies resulting in the restoration of articular cartilage that closely duplicates the native tissue. For cell-based therapies, the optimal cell source must be readily accessible with easily isolated, abundant cells capable of collagen type II and sulfated proteoglycan production in appropriate proportions. Although a cell source with these therapeutic properties remains elusive, mesenchymal chondroprogenitors retain their expansion capacity with the promise of reproducing the structural or biomechanical properties of healthy articular cartilage. As current knowledge regarding chondroprogenitors is relatively limited, this review will focus on their origin and therapeutic application. Keywords Articular CartilageNotch SignalingFibroblast Growth Factor ReceptorCartilage RepairChondrogenic Differentiation Introduction Osteoarthritis (OA) is a chronic disease of the joints characterized by progressive destruction of articular cartilage resulting in painful, limited joint movement. In the European Union over 39 million people exhibit symptoms of OA, a number anticipated to double in the next decade, creating an imperative for the timely development of effective treatments for the disease [1]. Current clinical therapies such as pharmaceutical interventions, bone marrow stimulation techniques or microfracture do not result in regeneration of healthy cartilage tissue [2, 3], but focus on the short-term relief of OA symptoms. When pharmaceutical intervention fails, clinicians regularly revert to invasive and permanent solutions. The first widely accepted regenerative treatment for cartilage repair was autologous chondrocyte transplantation. Despite its initial therapeutic promise, chondrocyte transplantation has associated complications, such as donor site morbidity, repair cell de-differentiation with expansion in vitro and restricted cellular life span upon implantation [4]. Immature progenitor cells with the potential to develop into mature tissues in response to appropriate cues have therefore become a primary focus of cartilage repair strategies as an alternative to chondrocyte-based methods [5]. The application of chondroprogenitors, cells that are specifically pre-disposed to differentiate into mature chondrocytes, to repair articular lesions and subsequently inhibit the onset of OA is a current focus of research efforts. As the mature articular joint develops from embryonic mesodermal precursors that differentiate into chondroprogenitors and ultimately into mature adult chondrocytes or synoviocytes, it is hypothesized that progenitors retained in these adult articular tissues provide a potential reservoir of chondroprogenitors. Development of the chondroprogenitor The development of the embryonic appendicular skeleton, whereby undifferentiated limb mesenchyme matures into a cartilaginous precursor and subsequently into bone, is dependent upon precursor exposure to specific combinations of morphogens and mechanical stimuli. Presumably a residual chondroprogenitor in the adult has been similarly primed and, when further stimulated, will respond by undergoing chondrogenic differentiation. Of critical importance during this developmental process are the transforming growth factor (TGF)-β, fibroblast growth factor (FGF), Wnt and Notch signaling pathways. In embryonic limb development, FGF-4 stimulates Sonic hedgehog (Shh) expression in a positive feedback loop that coordinates proximal-distal and anterior-posterior patterning of the cartilaginous anlagen, as was historically demonstrated in an avian model [6]. Shh, in turn, initiates a cascade of stimulatory molecules such as those of the TGF-β superfamily, thereby inducing mesenchymal differentiation into chondrocytes, as was originally demonstrated in murine limb mesenchyme [7]. Similarly, FGF-18 promotes cartilage formation in murine limb progenitor in vitro micromass cultures [8]. This effect is currently under clinical investigation for cartilage repair [9]. This phase I safety study assesses the ability of FGF-18 to stimulate chondrocyte development leading to the repair and regeneration of articular cartilage in patients undergoing knee replacement surgery. As FGF receptor isoform expression is highly regulated during each stage of embryonic human limb chondrogenesis [10], conserved FGF receptor expression patterns have been identified in embryonic chondrogenesis in vivo and progenitor cell differentiation in vitro, enabling a mechanism to compare tissue engineered cartilage with natural development [11]. Mesenchymal cell differentiation into chondrocytes, and the associated regulation of extracellular matrix (ECM) deposition, is minutely coordinated by paracrine factors. TGF-β and bone morphogenetic protein (BMP) signaling, often through Sox9 as a transcriptional mediator, are responsible for initiating expression of cartilaginous ECM such as aggrecan, collagen types II and XI, fibronectin and tenascin in in vitro murine micromass cultures [12, 13]. Opposing roles for the involvement of the mitogen-activated protein kinase signaling components ERK-1 and p38 downstream of TGF-β superfamily stimulation have been identified during in vitro chondrogenesis [14]; suppression of Erk-1/2 resulted in enhanced chondrogenesis whereas inhibition of p38 suppressed cartilage formation [15]. More specifically, inhibition of p38 si (...truncated)