Stem-Cell-Driven Chondrogenesis: Perspectives on Amnion-Derived Cells

Abstract

Regenerative medicine harnesses stem cells' capacity to restore damaged tissues and organs. In vitro methods employing specific bioactive molecules, such as growth factors, bio-inductive scaffolds, 3D cultures, co-cultures, and mechanical stimuli, steer stem cells toward the desired differentiation pathways, mimicking their natural development. Chondrogenesis presents a challenge for regenerative medicine. This intricate process involves precise modulation of chondro-related transcription factors and pathways, critical for generating cartilage. Cartilage damage disrupts this process, impeding proper tissue healing due to its unique mechanical and anatomical characteristics. Consequently, the resultant tissue often forms fibrocartilage, which lacks adequate mechanical properties, posing a significant hurdle for effective regeneration. This review comprehensively explores studies showcasing the potential of amniotic mesenchymal stem cells (AMSCs) and amniotic epithelial cells (AECs) in chondrogenic differentiation. These cells exhibit innate characteristics that position them as promising candidates for regenerative medicine. Their capacity to differentiate toward chondrocytes offers a pathway for developing effective regenerative protocols. Understanding and leveraging the innate properties of AMSCs and AECs hold promise in addressing the challenges associated with cartilage repair, potentially offering superior outcomes in tissue regeneration.

Keywords: amnion-derived cells; cartilage regeneration; chondrogenesis; stem cells; stem cells differentiation; tissue regeneration.

Figure 1

Comparative scientometric analysis of the available publications on the Scopus database found using the keywords “chondrogenesis”, “stem cell*”, “amnio*”, “epith*”, and “mesenchy*”: 7563 (51.3%) of the total publications on chondrogenesis concern stem cells. A deeper analysis of stem cells origin revealed that only 98 (1.3%) of the publications concern amnion-derived stem cells. Furthermore, 72 (73.5%) of the latter regard amniotic mesenchymal stem cells, 2 (2%) amniotic epithelial cells, and 11 (11.2%) concern both cell types.

Figure 2

Summary of pathways involved in chondrogenesis. (A) Molecules involved in the various phases of MSCs chondrogenesis. (B) Promoting and inhibitory factors that collaborate during MSCs chondrogenic differentiation via SOX9 expression. SRY-Box Transcription Factor (SOX); collagen (Col); Runt-related Transcription Factor 2 (RUNX2); Growth Differentiation Factor 5 (GDF5); Wingless-related integration site (Wnt); Small Mothers Against Decapentaplegic (SMAD); Transforming Growth Factor-beta (TGF-β); Bone Morphogenetic Protein (BMP); Indian Hedgehog (Ihh); Fibroblast Growth Factor (Fgf); Hypoxia Inducible Factor 1 Alpha (HIF1α); Hypoxia Inducible Factor 1 Beta (HIF1β); Histone Deacetylase 4 (HDAC4); oxygen (O₂); Extracellular Signal-Regulated Kinase (ERK); Sonic Hedgehog (Shh); NK3 Homeobox 2 (Nkx3.2); mesenchymal stromal cells (MSCs); Glioma-Associated Oncogenes (Gli); Noggin; Parathyroid Hormone-related Protein (PTHrP).

Figure 3

Summary of cartilage development. (A) Activation of chondrogenic signals thanks to mesoderm specification from Shh. (B) Beginning of cell condensation, stimulated by Gdf5 production. (C) Development of joints and activation of BMP antagonists. (D) Upregulation of FGF signalling to maintain cell specification along chondrogenesis. (E) Upregulation of HIF1α to further enhance the expression of chondro-related genes (Sox9, aggrecan, and collagen). Sonic Hedgehog (Shh); SRY-Box Transcription Factor 9 (Sox9); NK3 Homeobox 2 (Nkx3.2); Growth Differentiation Factor 5 (Gdf5); mesenchymal stromal cells (MSCs); Bone Morphogenetic Protein (BMP); Glycogen Synthase Kinase 3 Beta (GSK-3β); Casein Kinase 1 Alpha (CK1α); Adenomatous Polyposis Coli (APC); T-cell Factor (TCF)/Lymphoid Enhancer Factor (LEF); Fibroblast Growth Factor (FGF); Rat Sarcoma (RAS)-Guanosine Triphosphate (GTP); Rapid Accelerated Fibrosarcoma (Raf); Mitogen-Activated Protein Kinase (MEK); Extracellular Signal-Regulated Kinase (ERK); oxygen (O₂); Hypoxia Inducible factor (HIF); Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT); Hypoxia Response Element (HRE); hydroxyl group (OH).

Figure 4

Strategies for in vitro and in vivo induction of AECs’ and AMSCs’ chondrogenic differentiation. (A) Chondrogenic differentiation of AECs. (B) Chondrogenic differentiation of AMSCs. (C) Comparison of AECs, AMSCs, and ASCs chondrogenic potential. (D) In vivo chondrogenic differentiation of AMSCs in a mouse model after engraftment within abdominal muscles. (E) Recovery of osteoarthritic knee after hyaluronic acid and AMSCs injection in a rat model. The icons circled in green represent the best strategies for in vitro chondrogenic induction. Amniotic epithelial cells (AECs); amniotic mesenchymal stem cells (AMSCs); adipose-derived stem cells (ASCs); chondrogenic differentiation medium (DM); Transforming Growth Factor-beta (TGF-β); Bone Morphogenetic Protein (BMP); SRY-Box Transcription Factor 9 (SOX9); collagen II (ColII); hyaluronic acid (HA).