Infusion of Phagocytic Macrophages Overexpressing CPT1a Ameliorates Kidney Fibrosis in the UUO Model

Abstract

Phagocytosis is an inherent function of tissue macrophages for the removal of apoptotic cells and cellular debris during acute and chronic injury; however, the dynamics of this event during fibrosis development is unknown. We aim to prove that during the development of kidney fibrosis in the unilateral ureteral obstruction (UUO) model, there are some populations of macrophage with a reduced ability to phagocytose, and whether the infusion of a population of phagocytic macrophages could reduce fibrosis in the murine model UUO. For this purpose, we have identified the macrophage populations during the development of fibrosis and have characterized their phagocytic ability and their expression of CPT1a. Furthermore, we have evaluated the therapeutic effect of macrophages overexpressing CPT1a with high phagocytic skills. We evidenced that the macrophage population which exhibits high phagocytic ability (F4/80low-CD11b) in fibrotic animals decreases during the progression of fibrosis while the macrophage population with lower phagocytic ability (F4/80high-CD11b) in fibrotic conditions, conversely, increases and CPT1a macrophage cell therapy with a strengthening phagocytic ability is associated with a therapeutic effect on kidney fibrosis. We have developed a therapeutic approach to reduce fibrosis in the UUO model by enrichment of the kidney resident macrophage population with a higher proportion of exogenous phagocytic macrophages overexpressing CPT1a.

Macrophage-like THP-1 Cells Derived from High-Density Cell Culture Are Resistant to TRAIL-Induced Cell Death via Down-Regulation of Death-Receptors DR4 and DR5

“…The phagocytic activity was assessed after 2 h of cell incubation in growth medium supplemented with 1 mg/mL pHrodo Green E. coli [ 25 ]. To control the nonspecific staining, cells were incubated with 10 μg/mL of cytochalasin D for 30 min in a CO 2 incubator, then 1 mg/mL of pHrodo Green E. coli was added, and the incubation was continued for another 2 h. Fluorescence was measured with a BD Accuri C6 flow cytometer.…”

Development of Cell Therapies for Renal Disease and Regenerative Medicine

“…Moreover, it has been shown that in fibrotic conditions, the number of macrophages with a high phagocytic capacity decreases during the fibrosis progression whereas the macrophages with a lower phagocytic capacity, on the other hand, increased. Therefore, a cell therapy with macrophages overexpressing CPT1a with an increased phagocytic capacity administrated intravenously could counteract the decrease in phagocytic macrophages in the kidney, thus providing a therapeutic advantage against renal fibrosis [91].…”