Adipose, Bone Marrow and Synovial Joint-Derived Mesenchymal Stem Cells for Cartilage Repair

Abstract

Current cell-based repair strategies have proven unsuccessful for treating cartilage defects and osteoarthritic lesions, consequently advances in innovative therapeutics are required and mesenchymal stem cell-based (MSC) therapies are an expanding area of investigation. MSCs are capable of differentiating into multiple cell lineages and exerting paracrine effects. Due to their easy isolation, expansion, and low immunogenicity, MSCs are an attractive option for regenerative medicine for joint repair. Recent studies have identified several MSC tissue reservoirs including in adipose tissue, bone marrow, cartilage, periosteum, and muscle. MSCs isolated from these discrete tissue niches exhibit distinct biological activities, and have enhanced regenerative potentials for different tissue types. Each MSC type has advantages and disadvantages for cartilage repair and their use in a clinical setting is a balance between expediency and effectiveness. In this review we explore the challenges associated with cartilage repair and regeneration using MSC-based cell therapies and provide an overview of phenotype, biological activities, and functional properties for each MSC population. This paper also specifically explores the therapeutic potential of each type of MSC, particularly focusing on which cells are capable of producing stratified hyaline-like articular cartilage regeneration. Finally we highlight areas for future investigation. Given that patients present with a variety of problems it is unlikely that cartilage regeneration will be a simple "one size fits all," but more likely an array of solutions that need to be applied systematically to achieve regeneration of a biomechanically competent repair tissue.

Keywords: Mesenchymal stem cell (MSC); adipose tissue; articular cartilage; bone marrow; synovial joint; tissue engineering.

Figure 1

Schematic representation of the organization of articular cartilage. (A) Articular cartilage is a thin layer of hyaline tissue that covers the surface of bones in synovial joints. (B) The tissue is divided into four zones; the superficial (tangential), transitional, radial, and calcified zones. (C) The hyaline cartilage matrix can be subdivided by its composition around chondrocytes as pericellular, territorial and inter-territorial matrices. The collagens (primarily collagen type II, IX, and XI) provide tensile strength and the main proteoglycan, aggrecan, is responsible for compressive stiffness. Chondrocyte-matrix interactions are mediated through plasma membrane receptors such as integrins and CD44.

Figure 2

Mechanisms of MSC mediated repair. (A) Differentiation into replacement cell types. (B) Secretion of paracrine factors such as growth factors, cytokines, and hormones. Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), angiopoietin-1 (ANG1), interleukin-10 (IL-10), prostaglandin E₂ (PGE₂), nitrous oxide (NO), fibroblast growth factor (FGF-2), Transforming growth factor-beta (TGF-β), insulin-like growth factor-1 (IGF-1). (C) Transfer of organelles (e.g., mitochondria) and/or molecules through tunneling nanotubes. (D) Transfer of proteins/peptides, RNA, hormones, and/or chemicals by extracellular vesicles such as exosomes or microvesicles. Exosomes are generated through the endocytic pathway and released through exocytosis. Microvesicles are produced by cell surface budding and released directly from the plasma membrane. Adapted from Spees et al. (2016).

Figure 3

Schematic representation of the main tissue reservoirs of MSCs in the human body. MSCs have been found in the bone marrow, adipose tissue, articular cartilage, synovium, skeletal muscle, dental pulp, circulatory system, heart, brain, umbilical cord (including Wharton's jelly), and other connective tissues. Refer to text for further details.

Figure 4

Molecular regulation of chondrogenesis. MSCs are recruited to the future sites of cartilage formation. Following migration and local proliferation cell density increases (condensation). Cell-cell contacts trigger a set of intracellular signaling events which result in chondrogenesis accompanied by a change in cell morphology and cartilage ECM molecule secretion. A wide range of transcription factors regulated by soluble extracellular signaling molecules acting through the modulation of various protein kinases/phosphoprotein phosphatases play essential roles in the molecular control of chondrogenesis. See further details in text. Please note that this list is not exhaustive.