Myofibroblasts are a main cell-type of collagen-producing cells during tissue fibrosis, but their origins remains controversial. While bone marrow-derived myofibroblasts in renal fibrosis has been reported, the cell origin and mechanisms regulating their transition into myofibroblasts remain undefined. In the present study, cell lineage tracing studies by adoptive transfer of GFP+ or dye-labelled macrophages identified that monocyte/macrophages from bone marrow can give rise to myofibroblasts via the process of macrophage-myofibroblast transition (MMT) in a mouse model of unilateral ureteric obstruction. The MMT cells were a major source of collagen-producing fibroblasts in the fibrosing kidney, accounting for more than 60% of α-SMA+ myofibroblasts. The MMT process occurred predominantly within M2-type macrophages and was regulated by TGF-β/Smad3 signalling as deletion of Smad3 in the bone marrow compartment of GFP+ chimeric mice prevented the M2 macrophage transition into the MMT cells and progressive renal fibrosis. In vitro studies in Smad3 null bone marrow macrophages also showed that Smad3 was required for TGF-β1-induced MMT and collagen production. In conclusion, we have demonstrated that bone marrow-derived fibroblasts originate from the monocyte/macrophage population via a process of MMT. This process contributes to progressive renal tissue fibrosis and is regulated by TGF-β/Smad3 signalling.
In summary, the results of our meta-analysis indicate that maternal and paternal MTHFR gene C677T and A1298C polymorphisms are associated with RPL. We also observed a significant association between fetal MTHFR A1298C polymorphism and RPL but not C677T.
Aim: The appropriate selection of hospitalized patients for venous thromboembolism (VTE) prophylaxis is an important unresolved issue. We sought to validate the Caprini model, a famous individual VTE risk assessment model (RAM), in hospitalized Chinese patients. Methods: We performed a retrospective case-control study among unselected hospitalized patients admitted to a comprehensive hospital in China. A total of 347 patients were confirmed to have VTE during hospitalization, and 651 controls were randomly selected to match the patients according to medical service. Both the patients and controls were retrospectively assessed for the risk of VTE using the Caprini RAM. Results: The average Caprini cumulative risk score in the patients was significantly higher than that observed in the controls (4.69±2.58 vs 3.16±1.82, p<0.0001). Compared with that observed in the low-risk group, a classification of high-risk according to the Caprini model was associated with a 1.65-fold increased risk of VTE (95%CI 1.05-2.61), while that of highest-risk was associated with a 4.84-fold increased risk of VTE (95%CI 3.06-7.64). After further stratifying the highest risk level with a cumulative risk score of ≥ 5 into scores of 5-6, 7-8 and ≥ 9, the patients with a score of 5-6 were found to exhibit a 3.33-fold increased risk of VTE (95%CI 2.06-5.40), those with a score 7-8 exhibited a 9.41-fold increased risk of VTE (95%CI 4.90-18.08) and those with a score of ≥ 9 exhibited a 24.69-fold (95%CI 7.98-76.40) increased risk of VTE compared with their low-risk counterparts. Conclusions: Our study suggests that the Caprini RAM can be used to effectively stratify hospitalized Chinese patients into VTE risk categories based on individual risk factors. The classification of the highest risk level with a cumulative risk score of ≥ 5 provided significantly more clinical information, and further stratification of this group of patients is needed. J Atheroscler Thromb, 2014; 21:261-272.
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