CD34-negative mesenchymal stem-like cells may act as the cellular origin of human aortic valve calcification

Abstract

Although various osteogenic inducers contribute to the calcification of human aortic valve interstitial cells, the cellular origin of calcification remains unclear. We immunohistochemically investigated the cellular origin of valve calcification using enzymatically isolated cells from both calcified and non-calcified human aortic valve specimens. CD73-, 90-, and 105-positive and CD45-negative mesenchymal stem-like cells (MSLCs) were isolated from both types of valve specimens using fluorescence-activated cell sorting. MSLCs were further sorted into CD34-negative and -positive cells. Compared with CD34-positive cells, CD34-negative MSLCs were significantly more sensitive to high inorganic phosphate (3.2 mM), calcifying easily in response. Furthermore, immunohistochemical staining showed that significantly higher numbers (～7-9-fold) of CD34-negative compared with CD34-positive MSLCs were localized in calcified aortic valve specimens obtained from calcified aortic stenosis patients. These results suggest that CD34-negative MSLCs are responsible for calcification of the aortic valve.

Osteogenic potential of adipose mesenchymal stem cells is not correlated with aortic valve calcification

“…The "circulating stem cell theory" proposed that vessel calcification and in particular valve calcification might be mediated by circulating MSCs of various origin (Kuznetsov et al, 2001;Pal and Golledge, 2010;Boström, Rajamannan, and Towler, 2011;Gössl et al, 2012;Nomura et al, 2013;Furukawa, 2014;Boström, 2016). Our data suggest that at least adipose MSCs could hardly be such mediators as they completely lack the ability of osteogenic differentiation in CAVD patients.…”

Recent Advances in Research on Human Aortic Valve Calcification

“…1), via a BMP2-Dlx5-mediated pathway (27). Moreover, we observed that TNF-a reduces the expression of calcification inhibitors (28). Figure 2 summarizes the current hypothesis of how aortic valve calcification occurs in aortic valve interstitial cells (AVICs).…”

“…However, it has been suggested that these cells may work in undesirable ways in pathological conditions, such as in aortic valve calcification (44,45), fibrodysplasia ossificans progressiva (FOP) (46), ectopic ossification in spinal ligaments (47,48), and ectopic calcification following burn injury (49). Mesenchymal stem cells can cause improper calcification and ossification after differentiating into chondrocyte-or osteoblast-like cells according to environmental and local factors (48 -50 (28). We also found that CD34-negative MSLCs are more likely to cause hyperphosphate-induced calcification than CD34-positive MSLCs and were common in calcified valve tissue.…”

“…Furthermore, several signaling pathways downstream of TNF-a may be important. The NF-kB pathway, stimulated by TNF-a, plays an important role in calcification of cells from human aortic valve (27,28,73). Resveratrol (3, 5, 4′-trihydroxystilbene) is a naturally occurring compound that can modulate the risk of cardiovascular degenerative diseases (atherosclerosis) (80) and effectively suppresses NF-kB signaling by inhibiting the activities of NF-kB and IkB kinase (81).…”

Increased mesenchymal podoplanin expression is associated with calcification in aortic valves

“…Much of the positivity was seen specifically at the edges of small calcifications, 10 to 50 µm in diameter, tightly surrounding them and possibly representing active foci of calcification. Nomura and co-workers [33] have isolated mesenchymal stem-like cells (MSLCs) from both calcified and non-calcified human aortic valves. The CD34-negative MSLCs were more numerous in calcified valves and more sensitive to high inorganic phosphate-induced calcification than their CD34-positive counterparts, leading to the suggestion that these MSCLs are responsible for the calcification of the aortic valve.…”