Edward M. Conway

Genetic sequence of the Survivin GOF-IRES-mCherry mice generated

Stem cells (SC) and not progenitors (P) act as cells of origin of basal cell carcinoma (BCC). The mechanisms promoting BCC formation in SCs or restricting tumor development in Ps are currently unknown. In this study, we transcriptionally profiled SCs and Ps and found that Survivin, a pleiotropic factor that promotes cell division and inhibits apoptosis, was preferentially expressed in SCs. Using genetic gain- and loss-of-function mouse models, we showed that Survivin deletion in oncogene-expressing SCs prevents BCC formation. Survivin overexpression renders Ps competent to BCC formation by promoting cell survival and division while preventing apoptosis and differentiation. We identified Serum glucocorticoid–regulated kinase 1 (Sgk1) as a key downstream factor of Survivin and that its inhibition prevents BCC formation. This study uncovers the role and mechanisms by which Survivin regulates the competence of SCs to initiate BCC formation, promoting the survival of oncogene-expressing SCs and self-renewing division while restricting differentiation and apoptosis.Significance:This study identifies Survivin as a key regulator of the different ability of SCs and Ps to initiate skin cancer. Survivin expression in oncogene-targeted SCs is essential for their survival and self-renewal and to prevent their differentiation and apoptosis, allowing SCs and not Ps to initiate skin cancer.

Genetic sequence of the Survivin GOF-IRES-mCherry mice generated

Antithrombotic surfaces that prevent coagulation activation without interfering with haemostasis are required for blood-contacting devices. Such materials would restrain device-induced thrombogenesis and decrease the need for anticoagulant use, thereby reducing unwanted bleeding. Here, by optimizing the interactions with coagulation factor XII rather than preventing its surface adsorption, we develop a substrate-independent antithrombotic polymeric coating with sheltered positive charges. The antithrombic properties of the coating were demonstrated in vitro with human blood and in vivo using a carotid artery–jugular vein shunt model in rabbits. The coating exhibits a strong interaction with factor XII, but results in a low reciprocal activation of the contact pathway that triggers clot formation. These findings contradict the prevailing strategy of designing antithrombotic materials through protein-repelling surfaces. Overall, the polymeric coating we describe can benefit most blood-contacting devices and is a useful engineering guideline for designing surfaces with improved antithrombotic properties.

Stem cells (SC) and not progenitors (P) act as cells of origin of basal cell carcinoma (BCC). The mechanisms promoting BCC formation in SCs or restricting tumor development in Ps are currently unknown. In this study, we transcriptionally profiled SCs and Ps and found that Survivin, a pleiotropic factor that promotes cell division and inhibits apoptosis, was preferentially expressed in SCs. Using genetic gain- and loss-of-function mouse models, we showed that Survivin deletion in oncogene-expressing SCs prevents BCC formation. Survivin overexpression renders Ps competent to BCC formation by promoting cell survival and division while preventing apoptosis and differentiation. We identified Serum glucocorticoid–regulated kinase 1 (Sgk1) as a key downstream factor of Survivin and that its inhibition prevents BCC formation. This study uncovers the role and mechanisms by which Survivin regulates the competence of SCs to initiate BCC formation, promoting the survival of oncogene-expressing SCs and self-renewing division while restricting differentiation and apoptosis. Significance: This study identifies Survivin as a key regulator of the different ability of SCs and Ps to initiate skin cancer. Survivin expression in oncogene-targeted SCs is essential for their survival and self-renewal and to prevent their differentiation and apoptosis, allowing SCs and not Ps to initiate skin cancer.

Hemolytic-uremic syndrome (HUS) is a rare complication of an infection with Shiga toxin (Stx)-producing Escherichia coli (STEC-HUS), characterized by severe acute kidney injury, thrombocytopenia and microangiopathic hemolytic anemia, and specific therapy is still lacking. Thrombomodulin (TM) is a multi-domain transmembrane endothelial cell protein and its N-terminal domain has been implicated in the pathophysiology of some cases of HUS. Indeed, the administration of recombinant human TM (rhTM) may have efficacy in HUS. We used a Stx-based murine model of HUS to characterize the role of the N-terminal domain of TM. We show that mice lacking that domain (TMLed (−/−)) are more sensitive to Stx, with enhanced HUS progression seen at 4 days and increased mortality at 7 days post-HUS induction. In spite of these changes, renal function was less affected in surviving Stx-challenged TMLed (−/−) mice compared to their wild-type counterparts TMLed (+/+) at 7 days. Contrary to few clinical case reports from Japan, the administration of rhTM (0.06 mg/kg) to wild-type mice (C57BL/6J) with HUS did not protect against disease progression. This overall promising, but also contradictory body of evidence, requires further systematic preclinical and clinical investigations to clarify the role of TM in HUS as a potential therapeutic strategy.

Osteoarthritis (OA) is a prevalent form of arthritis that affects over 32.5 million adults worldwide, causing significant cartilage damage and disability. Unfortunately, there are currently no effective treatments for OA, highlighting the need for novel therapeutic approaches. Thrombomodulin (TM), a glycoprotein expressed by chondrocytes and other cell types, has an unknown role in OA. Here, we investigated the function of TM in chondrocytes and OA using various methods, including recombinant TM (rTM), transgenic mice lacking the TM lectin-like domain (TM^LeD/LeD), and a microRNA (miRNA) antagomir that increased TM expression. Results showed that chondrocyte-expressed TM and soluble TM [sTM, like recombinant TM domain 1 to 3 (rTMD123)] enhanced cell growth and migration, blocked interleukin-1β (IL-1β)-mediated signaling and protected against knee function and bone integrity loss in an anterior cruciate ligament transection (ACLT)-induced mouse model of OA. Conversely, TM^LeD/LeD mice exhibited accelerated knee function loss, while treatment with rTMD123 protected against cartilage loss even one-week post-surgery. The administration of an miRNA antagomir (miR-up-TM) also increased TM expression and protected against cartilage damage in the OA model. These findings suggested that chondrocyte TM plays a crucial role in counteracting OA, and miR-up-TM may represent a promising therapeutic approach to protect against cartilage-related disorders.