Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.
Objective:Robust arterial collaterals are associated with successful reperfusion after thrombectomy treatment of acute ischemic stroke due to large vessel occlusion (AIS-LVO). Excellent venous outflow (VO) reflects excellent tissue perfusion and collateral status in AIS-LVO patients. To determine whether favorable VO profiles assessed on pre-treatment CT angiography (CTA) images correlate with successful vessel reperfusion after thrombectomy in AIS-LVO patients.Methods:Multicenter retrospective cohort study of consecutive AIS-LVO patients treated by thrombectomy. Baseline CTA was used to assess collateral status (Tan scale) and VO using the cortical vein opacification score (COVES). Favorable VO was defined as COVES ≥3. Primary outcome was excellent vessel reperfusion status (modified Thrombolysis In Cerebral Infarction [TICI] 2c-3). Secondary outcome was good functional outcome defined as 0-2 on the Modified Ranking Scale (mRS) after 90 days.Results:565 patients met inclusion criteria. Multivariable logistic regression analysis showed that favorable VO (OR= 2.10 [95% CI 1.39-3.16]; p<0.001) was associated with excellent vessel reperfusion during thrombectomy, regardless of good CTA collateral status (OR= 0.87 [95%CI 0.58-1.34]; p=0.48). A favorable VO profile (OR= 8.9 [95%CI 5.3-14.9]; p<0.001) and excellent vessel reperfusion status (OR = 2.7 [95%CI 1.7-4.4]; p<0.001) were independently associated with good functional outcome adjusted for age, sex, glucose, tPA administration, good CTA collateral status and presentation NIHSS.Conclusion:A favorable VO profile is associated with reperfusion success and good functional outcomes in patients with AIS-LVO treated by endovascular thrombectomy.
Immunotherapy with anti-GD2 antibodies has advanced the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse, and little is known about mechanisms of resistance to anti-GD2 therapy. Here, we show that reduced GD2 expression was significantly correlated with the mesenchymal cell state in neuroblastoma and that a forced adrenergic-to-mesenchymal transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2-expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme
ST8SIA1
(GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of
ST8SIA1
, restoring surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.