The role of toll-like receptors in orchestrating osteogenic differentiation of mesenchymal stromal cells and osteoimmunology

Abstract

Osteoimmunology is a concept involving molecular and cellular crosstalk between the skeletal and immune systems. Toll-like receptors (TLRs) are widely expressed both on mesenchymal stromal cells (MSCs), the hematopoietic cells, and immune cells in the osteogenic microenvironment for bone development or repair. TLRs can sense both exogenous pathogen-associated molecular patterns (PAMPs) derived from microorganisms, and damage-associated molecular patterns (DAMPs) derived from normal cells subjected to injury, inflammation, or cell apoptosis under physiological or pathological conditions. Emerging studies reported that TLR signaling plays an important role in bone remodeling by directly impacting MSC osteogenic differentiation or osteoimmunology. However, how to regulate TLR signaling is critical and remains to be elucidated to promote the osteogenic differentiation of MSCs and new bone formation for bone tissue repair. This review outlines distinct TLR variants on MSCs from various tissues, detailing the impact of TLR pathway activation or inhibition on MSC osteogenic differentiation. It also elucidates TLR pathways’ interplay with osteoclasts, immune cells, and extracellular vesicles (EVs) derived from MSCs. Furthermore, we explore biomaterial-based activation to guide MSCs’ osteogenic differentiation. Therefore, understanding TLRs’ role in this context has significant implications for advancing bone regeneration and repair strategies.

Dental Stem Cells and Lipopolysaccharides: A Concise Review

“…TLRs are important mediators in inflammatory pathways and regulate migration or fate decisions in DTSCs [66,69]. After ligand binding, a cascade of signaling pathways, including cell type-dependent pathways through myeloid differentiation factor-88 (MyD88)-dependent, interferon b-dependent mitogen-activated protein pathway, TIR domain adapter kinase (MAPK)-inducing pathway, and phosphoinositide 3-kinase-Akt pathways, is triggered, which can influence proliferation, migration, and differentiation in MSCs and activate the expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) [50,70]. To date, the differential expression of 10 members of TLRs has been identified in MSCs, including TLR4, whose ligand is LPS [70].…”

The Role of Mesenchymal Stem/Stromal Cells in Head and Neck Cancer – Regulatory Mechanisms of Tumorigenic and Immune Activity, Chemotherapy Resistance, and Therapeutic Benefits of the Use of Stromal Cell-Based Pharmacological Strategies

“…It is known that MSCs with mainly pro-inflammatory effects are also activated during infections and early-stage inflammatory conditions. Exposure to TLR2 (peptidoglycan) from Gram-positive bacteria or TLR4 (LPS) from Gram negative bacteria encourages MSCs to migrate to the site of injury and promotes the immunity [160]. Thus, secretion of IL-6, IL-8, IFN-β, MIF and GM-CSF by MSCs may upregulate neutrophil migration to the site of infection or injury, enhancing their activation and phagocytosis whilst promoting their survival [144,161].…”