New Insights into Osteogenic and Chondrogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells and Their Potential Clinical Applications for Bone Regeneration in Pediatric Orthopaedics
Human mesenchymal stem cells (hMSCs) are pluripotent adult stem cells capable of being differentiated into osteoblasts, adipocytes, and chondrocytes. The osteogenic differentiation of hMSCs is regulated either by systemic hormones or by local growth factors able to induce specific intracellular signal pathways that modify the expression and activity of several transcription factors. Runt-related transcription factor 2 (Runx2) and Wnt signaling-related molecules are the major factors critically involved in the osteogenic differentiation process by hMSCs, and SRY-related high-mobility-group (HMG) box transcription factor 9 (SOX9) is involved in the chondrogenic one. hMSCs have generated a great interest in the field of regenerative medicine, particularly in bone regeneration. In this paper, we focused our attention on the molecular mechanisms involved in osteogenic and chondrogenic differentiation of hMSC, and the potential clinical use of hMSCs in osteoarticular pediatric disease characterized by fracture nonunion and pseudarthrosis. 1. Introduction Human mesenchymal stem cells (hMSCs) are pluripotent adult stem cells that can differentiate into different cell types of mesodermic origin, such as osteoblasts, adipocytes, and chondrocytes, as well as into other nonmesodermic cells [1, 2]. MSCs were first discovered by Friedenstein in 1968 as adherent fibroblast-like cells with multipotent differentiation capacities showing that clonal populations belonging to the colony forming unit-fibroblastoids (CFU-Fs) give rise to bone, cartilage, and hematopoietic supportive cells in vivo [1, 2]. MSCs have been originally isolated from bone marrow (BM); however, recently other tissues, such as adipose tissue, skeletal muscle, tendon, and trabecular bone, have been identified as potential sources of MSCs [1, 2]. Interestingly, the capacity of vascular pericytes, also known as mural cells that surround endothelial cells and express MSC stem cell markers, has been recently demonstrated in multiple human organs [3, 4]. These cells sustain long-term culture during which they express markers of mesenchymal stem cells and exhibit osteogenic, chondrogenic, and adipogenic potentials [3, 4], thus, supporting the hypothesis of a common perivascular origin of hMSC and postulating the existence of a ubiquitous reserve of multilineage progenitor cells in perivascular cells. hMSCs were generally defined based on their capacity to self-renew and on the phenotype of their culture amplified progeny because of the lack of a specific and stable cell marker expressed by these cells both
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