Categorization of scleroderma renal crisis (SRC) as hypertensive or normotensive can potentially overlook the underlying pathophysiology that might be unique in each patient, as they often exhibit a mixture of distinct pathological characteristics of narrowly defined SRC (nd-SRC) and systemic sclerosis associated thrombocytic micro-angiopathy (SSc-TMA). In this review, we provide evidence suggesting that better categorization of patients presenting with certain clinical features of both nd-SRC and TMA will improve treatment approaches. Based on our clinical experience and literature review, distinguishing between nd-SRC and SSc-TMA is important because the association of SSc-TMA with prior steroid administration and poor prognosis was stronger than that of nd-SRC. Although the two pathological entities cannot be easily distinguished based on blood pressure, we suggest that the detailed clinical course is helpful. Typically, nd-SRC exhibits prominently elevated blood pressure and worsening of renal function initially, followed by mild thrombocytopenia. Conversely, SSc-TMA presents first with severe thrombocytopenia, followed by elevated blood pressure and renal function deterioration. The degree of involvement in each pathological condition should be considered for determination of appropriate therapeutic interventions and prognostic prediction.

Angiogenesis is a multi‐step process that culminates in vascular maturation whereby nascent vessels stabilize to become functional, and mural cells play an essential role in this process. Recent studies have shown that mural cells in tumors also promote and maintain vascular integrity, with wide‐reaching clinical implications including the regulation of tumor growth, metastases, and drug delivery. Various regulatory signaling pathways have been hitherto implicated, but whether regulation of Fas‐dependent apoptotic mechanisms is involved has not yet been fully investigated. We first compared endothelial FAS staining in human pancreatic ductal adenocarcinomas and colon carcinomas and show that the latter, characterized by lower mural cell coverage of tumor vasculature, demonstrated higher expression of FAS than the former. Next, in an in vitro coculture system of MS‐1 and 10T1/2 cells as endothelial and mural cells respectively, we show that mural cells decreased endothelial Fas expression. Then, in an in vivo model in which C26 colon carcinoma cells were inoculated together with MS‐1 cells alone or with the further addition of 10T1/2 cells, we demonstrate that mural cells prevented hemorrhage. Finally, knockdown of endothelial Fas sufficiently recapitulated the protection against hemorrhage seen with the addition of mural cells. These results together suggest that regulation of endothelial Fas signaling is involved in the promotion of vascular integrity by mural cells in tumors.

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The phagocytosis of dead cells by microglia is essential in brain development and homeostasis. However, the mechanism underlying the efficient removal of cell corpses by ramified microglia remains poorly understood. Here, we investigated the phagocytosis of dead cells by ramified microglia in the hippocampal dentate gyrus, where adult neurogenesis and homeostatic cell clearance occur. Two-color imaging of microglia and apoptotic newborn neurons revealed two important characteristics.Firstly, frequent environmental surveillance and rapid engulfment reduced the time required for dead cell clearance. The motile microglial processes frequently contacted and enwrapped apoptotic neurons at the protrusion tips and completely digested them within 3-6 h of the initial contact. Secondly, while a single microglial process engaged in phagocytosis, the remaining processes continued environmental surveillance and initiated the removal of other dead cells. The simultaneous removal of multiple dead cells increases the clearance capacity of a single microglial cell. These two characteristics of ramified microglia contributed to their phagocytic speed and capacity, respectively. Consistently, the cell clearance rate was estimated to be 8-20 dead cells/microglia/day, supporting the efficiency of removing apoptotic newborn neurons. We concluded that ramified microglia specialize in utilizing individual motile processes to detect stochastic cell death events and execute parallel phagocytoses.