The chemerin/CMKLR1 axis regulates intestinal graft-versus-host disease

: Gastrointestinal graft-versus-host disease (GvHD) is a major cause of mortality and morbidity following allogeneic bone marrow transplantation (allo-BMT). Chemerin is a chemotactic protein that recruits leukocytes to inflamed tissues by interacting with ChemR23/CMKLR1, a chemotactic receptor expressed by leukocytes, including macrophages. During acute GvHD, chemerin plasma levels were strongly increased in allo-BM-transplanted mice. The role of the chemerin/CMKLR1 axis in GvHD was investigated using Cmklr1-KO mice. WT mice transplanted with an allogeneic graft from Cmklr1-KO donors (t-KO) had worse survival and more severe GvHD. Histological analysis demonstrated that the gastrointestinal tract was the organ mostly affected by GvHD in t-KO mice. The severe colitis of t-KO mice was characterized by massive neutrophil infiltration and tissue damage associated with bacterial translocation and exacerbated inflammation. Similarly, Cmklr1-KO recipient mice showed increased intestinal pathology in both allogeneic transplant and dextran sulfate sodium-induced colitis. Notably, the adoptive transfer of WT monocytes into t-KO mice mitigated GvHD manifestations by decreasing gut inflammation and T cell activation. In patients, higher chemerin serum levels were predictive of GvHD development. Overall, these results suggest that CMKLR1/chemerin may be a protective pathway for the control of intestinal inflammation and tissue damage in GvHD

GRN-/- iPSC-derived cortical neurons recapitulate the pathological findings of both frontotemporal lobar degeneration and neuronal ceroidolipofuscinosis

Heterozygous mutations in the gene coding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) while homozygous mutations are linked to neuronal ceroidolipofuscinosis (NCL). While both FTLD/NCL pathological hallmarks were mostly investigated in heterozygous GRN+/- brain tissue or iPSC-derived neurons, data from homozygous GRN-/- condition are scarce, being limited to a postmortem brain tissue from a single case. Indeed, homozygous GRN-/- is an extremely rare condition reported in very few cases. Our aim was to investigate pathological phenotypes associated to both FTLD and NCL in iPSC-derived cortical neurons from a GRN-/- patient affected by NCL. iPSCs were generated from peripheral blood of a GRN wt healthy donor and a GRN-/- patient and subsequently differentiated into cortical neurons. Several pathological changes were investigated, by means of immunocytochemical, biochemical and ultrastructural analyses. GRN-/- patient-derived cortical neurons displayed both TDP-43 and phospho-TDP-43 mislocalization, enlarged autofluorescent lysosomes and electron-dense vesicles containing storage material with granular, curvilinear and fingerprints profiles. In addition, different patterns in the expression of TDP-43, caspase 3 and cleaved caspase 3 were observed by biochemical analysis at different time points of cortical differentiation. At variance with previous findings, the present data highlight the existence of both FTLD- and NCL-linked pathological features in GRN-/- iPSC-derived cortical neurons from a NCL patient. They also suggest an evolution in the appearance of these features: firstly, FTLD-related TDP-43 alterations and initial NCL storage materials were detected; afterwards, mainly well-shaped NCL storage materials were present, while some FTLD features were not observed anymore

Mesenchymal stromal cells from Shwachman-Diamond syndrome patients fail to recreate a bone marrow niche in\ua0vivo and exhibit impaired angiogenesis

Shwachman-Diamond syndrome (SDS) is a rare multi-organ recessive disease mainly characterised by pancreatic insufficiency, skeletal defects, short stature and bone marrow failure (BMF). As in many other BMF syndromes, SDS patients are predisposed to develop a number of haematopoietic malignancies, particularly myelodysplastic syndrome and acute myeloid leukaemia. However, the mechanism of cancer predisposition in SDS patients is only partially understood. In light of the emerging role of mesenchymal stromal cells (MSCs) in the regulation of bone marrow homeostasis, we assessed the ability of MSCs derived from SDS patients (SDS-MSCs) to recreate a functional bone marrow niche, taking advantage of a murine heterotopic MSC transplant model. We show that the ability of semi-cartilaginous pellets (SCPs) derived from SDS-MSCs to generate complete heterotopic ossicles in\ua0vivo is severely impaired in comparison with HD-MSC-derived SCPs. Specifically, after in\ua0vitro angiogenic stimuli, SDS-MSCs showed a defective ability to form correct networks, capillary tubes and vessels and displayed a marked decrease in VEGFA expression. Altogether, these findings unveil a novel mechanism of SDS-mediated haematopoietic dysfunction based on hampered ability of SDS-MSCs to support angiogenesis. Overall, MSCs could represent a new appealing therapeutic target to treat dysfunctional haematopoiesis in paediatric SDS patients

The Look After Yourself (LAY) intervention to improve self-management in stroke survivors: Results from a quasi-experimental study

Objective: To test the efficacy of a self-management intervention for stroke survivors vs. usual care. Methods: Using a quasi-experimental study, participants were recruited from three public Italian hospitals. Questionnaires assessing self-efficacy (SSEQ), quality of life (SF-12), physical performance (SPPB), depression (GDS) and activities of daily living (MBI) were administered at baseline, discharge and two months after discharge. Mixed models with a propensity score were used between experimental group (EG) and control group (CG). Logistic models were used to compare the use of health services. Results: Eighty-two stroke survivors were enrolled in the EG and 103 in the CG. Self-efficacy in self-management improved in the EG compared to the CG during hospitalization. Improvements from baseline to discharge were found in the EG in the mental component of SF-12 and in MBI. The EG were 8.9 times more likely to contact general practitioners after discharge and 2.9 times to do regular exercise than CG. Notably, EG with higher education benefitted more from the intervention. Conclusion: The intervention was efficacious in improving self-efficacy, mental health and activities of daily living. Practice implications: Structured educational interventions based on problem-solving and individual goal setting may improve self-management skills in stroke survivors