Advanced Glycation End-Products Attenuate Human Mesenchymal Stem Cells and Prevent Cognate Differentiation Into Adipose Tissue, Cartilage, and Bone

Abstract

The impact of AGEs on human MSCs was studied. AGEs inhibited the proliferation of MSCs, induced apoptosis, and prevented cognate differentiation into adipose tissue, cartilage, and bone, suggesting a deleterious effect of AGEs in the pathogenesis of musculoskeletal disorders in aged and diabetic patients.Introduction: Advanced glycation end-products (AGEs) are accumulated on long-lived proteins of various tissues in advanced age and diabetes mellitus and have been implicated in chronic complication, including musculoskeletal disorders. Human mesenchymal stem cells (MSCs) potentially differentiate into mature musculoskeletal tissues during tissue repair, but the pathogenetic role of AGEs on MSCs is unclear. Materials and Methods: AGEs were prepared by incubating BSA with glucose, glyceraldehydes, or glycolaldehyde (designated as AGE-1, AGE-2, or AGE-3, respectively). Proliferation, apoptosis, and reactive oxygen species (ROS) generation were assayed in AGE-treated cells. The expression of the receptor for AGE (RAGE) was examined by immunohistochemistry and Western blotting. Involvement of RAGE-mediated signaling was examined using a neutralizing antiserum against RAGE. Differentiation into adipose tissue, cartilage, and bone were morphologically and biochemically monitored with specific markers for each. Results: AGE-2 and AGE-3, but not control nonglycated BSA and AGE-1, reduced the viable cell number and 5-bromo-2'deoxyuridine (BrdU) incorporation with increased intracellular ROS generation and the percentage of apoptotic cells. MSCs expressed RAGE and its induction was stimulated by AGE-2 and AGE-3. These AGEs inhibited adipogenic differentiation (assayed by oil red O staining, lipoprotein lipase production, and intracellular triglyceride content) and chondrogenic differentiation (assayed by safranin O staining and type II collagen production). On osteogenic differentiation, AGE-2 and AGE-3 increased alkaline phosphatase activity and intracellular calcium content; however, von Kossa staining revealed the loss of mineralization and mature bone nodule formation. The antiserum against RAGE partially prevented AGE-induced cellular events. Conclusion: AGE-2 and AGE-3 may lead to the in vivo loss of MSC mass and the delay of tissue repair by inhibiting the maturation of MSC-derived cells. The AGE-RAGE interaction may be involved in the deleterious effect of AGEs on MSCs.

Activated Platelets Interfere with Recruitment of Mesenchymal Stem Cells to Apoptotic Cardiac Cells via High Mobility Group Box 1/Toll-like Receptor 4-mediated Down-regulation of Hepatocyte Growth Factor Receptor MET

“…HMGB1 typically mediates recruitment of innate immune cells and stimulates inflammatory responses, such as release of proinflammatory cytokines through binding to receptors RAGE, TLR-2, and TLR-4 (32). Importantly, MSC express HMGB1 receptors (41,42), implying that MSC are a putative target for platelet-derived HMGB1. Enhanced (53) as well as reduced (42) migratory activity of MSC has been reported as a result of TLR ligation.…”

“…HMGB1 activates pattern recognition receptors Toll-like receptor (TLR)-4, TLR-2, and the receptor of advanced glycation end products (RAGE), a transmembrane multiligand receptor of the immunoglobulin superfamily (39,40). MSC have been reported to express these receptors for HMGB1 (41,42), implying that MSC might be a putative target of platelet-derived HMGB1 in the process of MSC recruitment to injured cardiac cells.…”

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

“…It has recently been reported that AGEs stimulate apoptosis of human mesenchymal stem cells which could limit the formation of adipose tissue, cartilage and bone (25). Other parameters may also be affected including AGE-inhibited proliferation and differentiation (33).…”

S100A4 and Uric Acid Promote Mesenchymal Stromal Cell Induction of IL-10+/IDO+ Lymphocytes

“…First, S100A4 is overexpressed in colorectal carcinomas, and elevated S100A4 levels are associated with a poor prognosis (19,20). Second, RAGE, the extracellular receptor for S100A4, is expressed on MSCs (26). We could also show that depletion of RAGE ligands within necrotic material could significantly reduce the effect of tumor lysates on MSCs (2).…”

“…The receptor for advanced glycation end products (RAGE) (19,22), the epidermal growth factor receptor (EGFR) (23), and TLR4 (24,25) are extracellular receptors for S100 proteins. All three receptors are expressed on MSCs (23,(26)(27)(28).…”