The polarization of monocytes into macrophages that possess anti-inflammatory and proangiogenic properties could provide a novel therapeutic strategy for patients who are at a high risk for developing heart failure following myocardial infarction (MI). Here in, we describe a novel method of "educating" monocytes into a distinct population of macrophages that exhibit antiinflammatory and pro-angiogenic features through a 3-day culture on fibronectin-rich cardiac matrix (CX) manufactured using cultured human cardiac fibroblasts. Our data suggest that CX can educate monocytes into a unique macrophage population termed CX educated macrophages (CXMq) that secrete high levels of VEGF and IL-6. In vitro, CXMq also demonstrate the ability to recruit mesenchymal stromal cells (MSC) with known anti-inflammatory properties. Selective inhibition of fibronectin binding to αVβ3 surface integrins on CXMq prevented MSC recruitment. This suggests that insoluble fibronectin within CX is, at least in part, responsible for CXMq conversion.
18F-DCFPyl is a Food and Drug Administration–approved radiotracer that targets prostate-specific membrane antigen and is used in the detection of recurrent or metastatic prostate cancer. As its use has increased, a growing number of nonprostatic disease entities have been identified that express prostate-specific membrane antigen and can mimic prostate cancer. Thus, the interpreting physician must also consider other variables such as serum prostate-specific antigen levels and the distribution of uptake to avoid an inappropriate diagnosis of metastatic prostate cancer. We describe 18F-DCFPyl uptake associated with a hepatic small vessel neoplasm, an association previously undescribed in the literature.
Introduction:
Polarizing monocytes into macrophages that possess anti-inflammatory and angiogenic properties could be cardio-reparative following myocardial infarction. Co-culturing cardiac fibroblasts (CF) with monocytes is observed to lead to alternatively activated macrophages. We previously showed that CF produce a unique cardiac matrix (CX) that is fibronectin enriched. Whether decellularized CX can drive differentiation of monocytes to macrophages with angiogenic and anti-inflammatory properties is unknown.
Hypotheses:
(i) CX educated macrophages (CXMq) that secrete VEGF and IL-6, which have known angiogenic and anti-inflammatory properties respectively, (ii) CXMq can recruit mesenchymal stromal cells (MSC), which have known anti-inflammatory properties and (iii) fibronectin is responsible for this effect.
Methods:
Human monocytes (CD14
+
) were cultured on CX, plastic and gelatin. After 3 days, flow expression of the macrophage markers CD14, CD16, CD163, CD206, PDL1, CD86, and HLA-DR was measured. VEGF and IL-6 levels were measured from the spent media. A transwell migration assay was performed by placing monocytes on CX in the lower chamber and MSC in the upper chamber. CX was enzymatically dispersed and flow cytometry was performed for CD14 (macrophage marker) and CD73 (MSC marker). Migration was defined as the % of MSCs reaching the lower chamber (see Figure). Controls included monocytes plated on plastic, and monocyte/CX combination cultured with and without fibronectin integrin receptor inhibitor.
Results:
CXMq secreted high levels of VEGF and IL-6 and also had low expression of inflammatory markers CD16, CD86, HLADR. Further, CXMq recruited MSC more robustly than monocytes and CX alone (see Figure). Selective fibronectin integrin receptor blockade prevented MSC recruitment (*p<0.05).
Conclusions:
CXMq has anti-inflammatory and pro-angiogenic properties that is potentially mediated by fibronectin.
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