Abstract
Pyrophosphate-containing calcium phosphate implants promote osteoinduction and bone regeneration. The role of pyrophosphate for inflammatory cell-mesenchymal stem cell (MSC) cross-talk during osteogenesis is not known. In the present work, the effects of lipopolysaccharide (LPS) and pyrophosphate (PPi) on primary human monocytes and on osteogenic gene expression in human adipose-derived MSCs were evaluated in vitro, using conditioned media transfer as well as direct effect systems. Direct exposure to pyrophosphate increased nonadherent monocyte survival (by 120% without LPS and 235% with LPS) and MSC viability (LDH) (by 16–19% with and without LPS). Conditioned media from LPS-primed monocytes significantly upregulated osteogenic genes (ALP and RUNX2) and downregulated adipogenic (PPAR-γ) and chondrogenic (SOX9) genes in recipient MSCs. Moreover, the inclusion of PPi (250 μM) resulted in a 1.2- to 2-fold significant downregulation of SOX9 in the recipient MSCs, irrespective of LPS stimulation or culture media type. These results indicate that conditioned media from LPS-stimulated inflammatory monocytes potentiates the early MSCs commitment towards the osteogenic lineage and that direct pyrophosphate exposure to MSCs can promote their viability and reduce their chondrogenic gene expression. These results are the first to show that pyrophosphate can act as a survival factor for both human MSCs and primary monocytes and can influence the early MSC gene expression.Graphical abstract
Highlights
Bone tissue has a remarkable ability to regenerate following injury
Circulating monocytes are actively recruited to an injury site [1, 4] where they differentiate into macrophages that recruit and activate multiple cell types
The amount of adherent mesenchymal stem cell (MSC) in the wells after 72 h of incubation in the assigned media was similar between all conditions and inflammatory status and was not affected by PPi (Online Resource 1 (Supplementary Table S2))
Summary
Bone tissue has a remarkable ability to regenerate following injury. malunion or nonunion still occurs in more than 10% of traumatic injury cases [1], especially when the degree of injury exceeds the body’s ability to repair or when the healing is compromised. Monocytes/macrophages express and secrete biological mediators that recruit mesenchymal stem cells (MSCs) [5] and osteoblasts [6]. Progenitors from the monocytic lineage can directly differentiate into bone-resorbing osteoclasts [6] and can polarize towards pro-inflammatory (M1) or pro-regenerative (M2) macrophage phenotypes [7,8,9]. In addition to their role during the acute healing phase, it has been suggested that signals secreted by macrophages modulate the regenerative process even after the initial inflammatory response is resolved [8, 9]. Another study concluded that materialinduced M2 macrophages stimulate the proliferation and differentiation of MSCs, leading to improved vascularization and angiogenic gene expression [11]
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