Renal Macrophages and Multinucleated Giant Cells: Ferrymen of the River Styx?

Sivaguru, Mayandi; Fouke, Bruce W.

doi:10.34067/kid.0003992022

Cited by 1 publication

(1 citation statement)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous cellular and molecular pathophysiology studies propose that calcification is initiated by external damage and scarring of the VEC and outermost fibrosa layer due to oxidative and biomechanical stress 7 , 11 – 15 , 23 , 24 . In this widely held scenario, ACP-saturated and water-rich blood serum solutions containing lipoproteins and immune cells would infiltrate through these damaged breeches, in a manner similar to that of saturated urine in the thin loops of Henle during human kidney stone formation 73 . Resulting inflammation would activate reactive oxygen species, monocytes and macrophages (multinucleated giant cells) and cause VICs to differentiate into fibroblast, osteoblast-like and SMC myofilament phenotypes that promote fibrosis, calcification, matrix remodeling and leaflet stenosis.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin stabilization and collagen containment slows amorphous calcium phosphate transformation during human aortic valve leaflet calcification

Sivaguru,

Mori,

Fouke

et al. 2024

Sci Rep

Self Cite

View full text Add to dashboard Cite

Calcification of aortic valve leaflets is a growing mortality threat for the 18 million human lives claimed globally each year by heart disease. Extensive research has focused on the cellular and molecular pathophysiology associated with calcification, yet the detailed composition, structure, distribution and etiological history of mineral deposition remains unknown. Here transdisciplinary geology, biology and medicine (GeoBioMed) approaches prove that leaflet calcification is driven by amorphous calcium phosphate (ACP), ACP at the threshold of transformation toward hydroxyapatite (HAP) and cholesterol biomineralization. A paragenetic sequence of events is observed that includes: (1) original formation of unaltered leaflet tissues: (2) individual and coalescing 100’s nm- to 1 μm-scale ACP spherules and cholesterol crystals biomineralizing collagen fibers and smooth muscle cell myofilaments; (3) osteopontin coatings that stabilize ACP and collagen containment of nodules preventing exposure to the solution chemistry and water content of pumping blood, which combine to slow transformation to HAP; (4) mm-scale nodule growth via ACP spherule coalescence, diagenetic incorporation of altered collagen and aggregation with other ACP nodules; and (5) leaflet diastole and systole flexure causing nodules to twist, fold their encasing collagen fibers and increase stiffness. These in vivo mechanisms combine to slow leaflet calcification and establish previously unexplored hypotheses for testing novel drug therapies and clinical interventions as viable alternatives to current reliance on surgical/percutaneous valve implants.

show abstract