Segmented platelets
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Beclin 1 of megakaryocytic lineage cells is locally dispensable for platelet hemostasis but functions distally in bone homeostasis
The crosstalk between megakaryocytic lineage cells and the skeletal system has just begun to be explored but remains largely elusive. Using conditional gene knockout mouse models, we demonstrated that loss of Beclin 1 (Becn1), a major regulator of mammalian autophagy, exclusively in the megakaryocytic lineage disrupted autophagy in platelets but did not compromise megakaryopoiesis or the formation and function of platelets. Unexpectedly, conditional Becn1 deletion in male mice led to a remarkable increase in bone mass with improved bone quality, in association with a decrease in sex hormone binding globulin (SHBG) and an increase in free testosterone (FT). In vivo Becn1 overexpression in megakaryocytic lineage-specific cells reduced bone mass and quality, along with an increase in SHBG and a decrease in FT. Transplantation of wild-type bone marrow cells into megakaryocytic lineage Becn1-deficient male mice restored bone mass and normalized SHBG and FT. Furthermore, bilateral orchiectomy of Becn1f/f;Pf4-iCre mice, which are crippled with the production of testosterone, resulted in a reduction in bone mass and quality, whereas in vivo overexpression of SHBG, specifically in the liver of Becn1f/f;Pf4-iCre mice, decreased FT and reduced bone mass and quality. In addition, metformin treatment, which induces SHBG expression, reduced FT and normalized bone mass in Becn1f/f;Pf4-iCre mice. We thus concluded that Becn1 of the megakaryocytic lineage is dispensable locally for platelet hemostasis but limits bone mass by increasing SHBG, which in turn reduces the FT of male mice. Our findings highlight a mechanism by which Becn1 from megakaryocytic lineage cells distally balances bone growth.
Extravascular coagulation regulates haemostasis independently of activated platelet surfaces in an in vivo mouse model
While the conventional understanding of haemostatic plug formation is that coagulation proceeds efficiently on the surface of activated platelets at the vascular injury site to form a robust haemostatic plug, this understanding does not explain the clinical reality that platelet dysfunction results in a mild bleeding phenotype, whereas coagulation disorders exhibit severe bleeding phenotypes, particularly in deep tissues. Here, we introduce an in vivo imaging method to observe internal bleeding and subsequent haemostatic plug formation in mice and report that haemostatic plug formation after internal bleeding, coagulation occurs primarily outside the blood vessel rather than on platelets. Experiments in mice with impaired platelet surface coagulation, depleted platelets, haemophilia A or reduced tissue factor expression suggest that this extravascular coagulation triggers and regulates haemostatic plug formation. Our discovery of the important role of extravascular coagulation in haemostasis may contribute to refining the treatment of haemostatic abnormalities and advancing antithrombotic therapy.
Direct preparation of two-dimensional platelets from polymers enabled by accelerated seed formation
Crystallization-driven self-assembly (CDSA) presents a facile method to access well-defined nanostructures. However, nanostructure preparation via CDSA has been constrained by prolonged processing time and limited throughput, primarily due to seed preparation and confinement to small batch scales. In turn, this limits the potential to scale up CDSA to enable application of the resultant particles. Here we report a rapid seed preparation method that drives uniform seed micelle formation by supersaturating polymer solutions in a flow system. This leads to a large reduction in processing time, from a week down to minutes. Importantly, the modular flow cascade applied can integrate both seed preparation and living CDSA, enabling end-to-end production of nanostructures directly from polymers in 3 min. The attained throughput of 132 mg h−1 surpasses that of other reported methods by orders of magnitude and, in turn, provides a step forward for the scaling-up of precision nanomaterials.
Bicomponent nano- and microfiber aerogels for effective management of junctional hemorrhage
Managing junctional hemorrhage is challenging due to ineffective existing techniques, with the groin being the most common site, accounting for approximately 19.2% of potentially survivable field deaths. Here, we report a bicomponent nano- and microfiber aerogel (NMA) for injection into deep, narrow junctional wounds to effectively halt bleeding. The aerogel comprises intertwined poly(lactic acid) nanofibers and poly(ε-caprolactone) microfibers, with mechanical properties tunable through crosslinking. Optimized aerogels demonstrate improved resilience, toughness, and elasticity, enabling rapid re-expansion upon blood contact. They demonstrate superior blood absorption and clotting efficacy compared to commercial products (i.e., QuikClot® Combat Gauze and XStat®). Most importantly, in a lethal swine junctional wound model (Yorkshire swine, both male and female, n = 5), aerogel treatment achieved immediate hemostasis, a 100% survival rate, no rebleeding, hemodynamic stability, and stable coagulation, hematologic, and arterial blood gas testing.
Periodontitis impacts on thrombotic diseases: from clinical aspect to future therapeutic approaches
Periodontitis is a chronic inflammatory disease initiated by biofilm microorganisms and mediated by host immune imbalance. Uncontrolled periodontal infections are the leading cause of tooth loss in adults. Thrombotic diseases can lead to partial or complete obstruction of blood flow in the circulatory system, manifesting as organ or tissue ischemia and necrosis in patients with arterial thrombosis, and local edema, pain and circulatory instability in patients with venous thrombosis, which may lead to mortality or fatality in severe case. Recent studies found that periodontitis might enhance thrombosis through bacterial transmission or systemic inflammation by affecting platelet-immune cell interactions, as well as the coagulation, and periodontal therapy could have a prophylactic effect on patients with thrombotic diseases. In this review, we summarized clinical findings on the association between periodontitis and thrombotic diseases and discussed several novel prothrombotic periodontitis-related agents, and presented a perspective to emphasize the necessity of oral health management for people at high risk of thrombosis.
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