scholarly journals Microglial replacement therapy: a potential therapeutic strategy for incurable CSF1R-related leukoencephalopathy

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Jinming Han ◽  
Heela Sarlus ◽  
Zbigniew K. Wszolek ◽  
Virginija Danylaité Karrenbauer ◽  
Robert A. Harris
Keyword(s):  
Therapeutic Strategy ◽  
Clinical Symptoms ◽  
Gene Mutations ◽  
Research Field ◽  
Hematopoietic Stem ◽  
Axonal Spheroids ◽  
Medical Need ◽  
The Central Nervous System ◽  
Stimulating Factor

AbstractCSF1R-related leukoencephalopathy is an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia caused by colony stimulating factor 1 receptor (CSF1R) gene mutations. The disease has a global distribution and currently has no cure. Individuals with CSF1R-related leukoencephalopathy variably present clinical symptoms including cognitive impairment, progressive neuropsychiatric and motor symptoms. CSF1R is predominantly expressed on microglia within the central nervous system (CNS), and thus CSF1R-related leukoencephalopathy is now classified as a CNS primary microgliopathy. This urgent unmet medical need could potentially be addressed by using microglia-based immunotherapies. With the rapid recent progress in the experimental microglial research field, the replacement of an empty microglial niche following microglial depletion through either conditional genetic approaches or pharmacological therapies (CSF1R inhibitors) is being studied. Furthermore, hematopoietic stem cell transplantation offers an emerging means of exchanging dysfunctional microglia with the aim of reducing brain lesions, relieving clinical symptoms and prolonging the life of patients with CSF1R-related leukoencephalopathy. This review article introduces recent advances in microglial biology and CSF1R-related leukoencephalopathy. Potential therapeutic strategies by replacing microglia in order to improve the quality of life of CSF1R-related leukoencephalopathy patients will be presented.

scholarly journals Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

2021 ◽  
Vol 13 ◽  
Author(s):  
Banglian Hu ◽  
Shengshun Duan ◽  
Ziwei Wang ◽  
Xin Li ◽  
Yuhang Zhou ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurological Disorders ◽  
Neurological Diseases ◽  
Colony Stimulating Factor ◽  
Loss Of Function ◽  
Axonal Spheroids ◽  
The Central Nervous System ◽  
Stimulating Factor

The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer’s disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

scholarly journals A csf1rb mutation uncouples two waves of microglia development in zebrafish

Development ◽  
2020 ◽  
pp. dev.194241
Author(s):  
Giuliano Ferrero ◽  
Magali Miserocchi ◽  
Elodie Di Ruggiero ◽  
Valérie Wittamer
Keyword(s):  
Central Nervous System ◽  
Adult Population ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Mapping Strategy ◽  
The Central Nervous System ◽  
Evolutionary Aspects ◽  
Stimulating Factor ◽  
Specific Contribution

In vertebrates, the ontogeny of microglia, the resident macrophages of the central nervous system, initiates early during development from primitive macrophages. While murine embryonic microglia then persist through life, in zebrafish these cells are transient, as they are fully replaced by an adult population originating from larval hematopoietic stem cell (HSC)-derived progenitors. Colony-stimulating factor receptor 1 (csf1r) is a fundamental regulator of microglia ontogeny in vertebrates, including zebrafish which possess two paralogous genes: csf1ra and csf1rb. While previous work showed mutation in both genes completely abrogates microglia development, the specific contribution of each paralog remains largely unknown. Here, using a fate-mapping strategy to discriminate between the two microglial waves, we uncover non-overlapping roles for csf1ra and csf1rb in hematopoiesis, and identified csf1rb as an essential regulator of adult microglia development. Notably, we demonstrate that csf1rb positively regulates HSC-derived myelopoiesis, resulting in macrophage deficiency, including microglia, in adult mutant animals. Overall, this study contributes to new insights into evolutionary aspects of Csf1r signaling and provides an unprecedented framework for the functional dissection of embryonic versus adult microglia in vivo.

scholarly journals Relapsed Primary Central Nervous System Lymphoma: Current Advances

2021 ◽  
Vol 11 ◽  
Author(s):  
Kaiyan Tao ◽  
Xuefeng Wang ◽  
Xin Tian
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Escape ◽  
Clinical Symptoms ◽  
Central Nervous System Lymphoma ◽  
Complete Response ◽  
High Dose ◽  
Related Factors ◽  
Hematopoietic Stem ◽  
The Central Nervous System

Primary central nervous system lymphoma is an invasive malignant lymphoma confined to the central nervous system. Although patients undergoing first-line treatment can achieve complete response, most of them still relapse within two years. Relapsed lymphoma is derived from occult lymphoma cells, and B cell receptor pathway activation and immune escape are the key mechanisms for the pathogenesis of PCNSL. Most relapses are in the central nervous system, a small number of relapses are isolated systemic relapses, and clinical symptoms occur early and vary. Current treatments for relapse include high-dose methotrexate rechallenge and other regimens of chemotherapy, whole-brain radiation therapy, hematopoietic stem-cell transplantation, targeted therapy and immunotherapy, which have become promising treatments. The overall prognosis of relapsed PCNSL is very poor, although it is affected by many factors. This article summarizes the mechanisms, related factors, clinical features, follow-up, treatment and prognosis of relapsed primary central nervous system lymphoma.

scholarly journals Multiplication of the Enterocyte Mass by Serosal Patch Technique / Umnožavanje Enterocitne Mase Tehnikom Seroznog Patch-A

2015 ◽  
Vol 65 (2) ◽  
pp. 162-174
Author(s):  
P. Slobodan Grebeldinger ◽  
S. Branka Radojčić ◽  
N. Jelena Ćulafić ◽  
M. Bojana Andrejić Višnjić
Keyword(s):  
Small Intestine ◽  
Control Group ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Patch Technique ◽  
Stimulating Factor

Abstract Damage to the small intestine and impairment of the intestinal epithelium occur in various diseases, resulting in a need for new epithelium. Therefore, bioengineering of the small intestine is becoming an attractive field of research where all contributions are highly appreciated. The purpose of this study was to determine the possibility of the multiplication of the enterocyte mass using the technique of serosal patch with the application of hematopoietic stem cells, as well as the assessment of the quality of newly formed mucosa. Sixty Mill Hill hooded rats were divided in 4 groups, 15 animals each. In the control group animals, the patch was not created. In the other three groups, the animals were operated on and in each group 8 parietal and 7 visceral patches have been created. One of the groups with operated animals (Group NS) was not postoperatively treated. The second group of operated animals (Group G) was stimulated with granulocyte colony-stimulating factor (G-CSF). The third group of operated animals (Group GM) was stimulated with recombined humane granulocyte-macrophage colony-stimulating factor (rHuGM-CSF). In the group of animals that were not stimulated, epithelium proliferated slowly. In the group of animals stimulated with G-CSF stimulants, the epithelium initially proliferated rapidly, but appeared atrophic after eight weeks. Stimulation by rHuGM-CSF led to faster epithelization, and epithelium showed signs of advancing proliferation after eight weeks. We confirmed the possibility of enterocyte mass multiplication by using the serosal patch technique, as well as that stimulation with rHuGM-CSF is more effective than stimulation with G-CSF.

scholarly journals Circulating CircRNAs Panel Acts as a Biomarker for the Early Diagnosis and Severity of Parkinson’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Lingling Zhong ◽  
KeJu Ju ◽  
Ainian Chen ◽  
Hua Cao
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Diagnosis ◽  
Disease Progression ◽  
Clinical Symptoms ◽  
Early Stage ◽  
Healthy Controls ◽  
Training Set ◽  
The Central Nervous System

Parkinson’s disease (PD) is a chronic and progressive degenerative disease of the central nervous system. Degenerative neuropathy can occur in patients with PD even before typical clinical symptoms appear in the preclinical stage. Therefore, if the early diagnosis of degenerative diseases can be timely and the correlation with the disease progression can be explored, the disease progression will be slowed down and the quality of life of patients will be improved. In this study, the circRNA microarray was employed to screen the dysregulated circRNA in plasma samples of PD. Four circRNAs (circ_0085869, circ_0004381, circ_0017204, and circ_0090668) were obtained with increased levels in PD patients by cross comparison and preliminary verification in PD comparing with healthy controls. Further validation found the circRNA panel was consistent with the training set. The ROC curve also revealed a high diagnostic ability of circ_0004381 and circ_0017204 in predicting the early stage of PD from healthy controls. circ_0085869, circ_0004381, circ_0017204, and circ_0090668 also presented a high ability to distinguish the late stage of PD from early stage. In conclusion, circulating circRNA panel might be a potential fingerprint for predicting the early diagnosis of PD and may act as a biomarker for disease progression.

scholarly journals Altered Functions of Neutrophils in Two Chinese Patients With Severe Congenital Neutropenia Type 4 Caused by G6PC3 Mutations

2021 ◽  
Vol 12 ◽  
Author(s):  
Rongxin Dai ◽  
Ge Lv ◽  
Wenyan Li ◽  
Wenjing Tang ◽  
Junjie Chen ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Neutrophil Function ◽  
Chinese Patients ◽  
Hematopoietic Stem ◽  
Oral Ulcers ◽  
Before And After ◽  
Choice Of Treatment ◽  
Inflammatory Bowel ◽  
Stimulating Factor

BackgroundSCN4 is an autosomal recessive disease caused by mutations in the G6PC3 gene. The clinical, molecular, and immunological features; function of neutrophils; and prognosis of patients with SCN4 have not been fully elucidated.MethodsTwo Chinese pediatric patients with G6PC3 mutations were enrolled in this study. Clinical data, genetic and immunologic characteristics, and neutrophil function were evaluated in patients and controls before and after granulocyte colony-stimulating factor (G-CSF) treatment.ResultsBoth patients had histories of pneumonia, inguinal hernia, cryptorchidism, and recurrent oral ulcers. Patient 1 also had asthma and otitis media, and patient 2 presented with prominent ectatic superficial veins and inflammatory bowel disease. DNA sequencing demonstrated that both patients harbored heterozygous G6PC3 gene mutations. Spontaneous and FAS-induced neutrophil apoptosis were significantly increased in patients, and improved only slightly after G-CSF treatment, while neutrophil respiratory burst and neutrophil extracellular traps production remained impaired in patients after G-CSF treatment.ConclusionG-CSF treatment is insufficient for patients with SCN4 patients, who remain at risk of infection. Where possible, regular G-CSF treatment, long-term prevention of infection, are the optimal methods for cure of SCN4 patients. It is important to monitor closely for signs of leukemia in SCN4 patients. Once leukemia occurs in SCN4 patients, hematopoietic stem cell transplantation is the most important choice of treatment.

scholarly journals Csf1rb mutation uncouples two waves of microglia development in zebrafish

2020 ◽  
Author(s):  
Giuliano Ferrero ◽  
Magali Miserocchi ◽  
Elodie Di Ruggiero ◽  
Valérie Wittamer
Keyword(s):  
Central Nervous System ◽  
Adult Population ◽  
Colony Stimulating Factor ◽  
Hematopoietic Stem ◽  
Mapping Strategy ◽  
The Central Nervous System ◽  
Evolutionary Aspects ◽  
Stimulating Factor ◽  
Specific Contribution

ABSTRACTIn vertebrates, the ontogeny of microglia, the resident macrophages of the central nervous system, initiates early during development from primitive macrophages. While murine embryonic microglia then persist through life, in zebrafish these cells are transient, as they are fully replaced by an adult population originating from larval hematopoietic stem cell (HSC)-derived progenitors. Colony-stimulating factor receptor 1 (csf1r) is a fundamental regulator of microglia ontogeny in vertebrates, including zebrafish which possess two paralogous genes: csf1ra and csf1rb. While previous work showed invalidation of both genes completely abrogates microglia development, the specific contribution of each paralog remains largely unknown. Here, using a fate-mapping strategy to discriminate between the two microglial waves, we uncover non-overlapping roles for csf1ra and csf1rb in hematopoiesis, and identified csf1rb as an essential regulator of adult microglia development. Notably, we demonstrate that csf1rb positively regulates HSC-derived myelopoiesis, resulting in macrophage deficiency, including microglia, in adult mutant animals. Overall, this study contributes to new insights into evolutionary aspects of Csf1r signaling and provides an unprecedented framework for the functional dissection of embryonic versus adult microglia in vivo.

scholarly journals Kostmann Syndrome With Neurological Abnormalities: A Case Report and Literature Review

2020 ◽  
Vol 8 ◽  
Author(s):  
Baiyu Lyu ◽  
Wei Lyu ◽  
Xiaoying Zhang
Keyword(s):  
Gene Mutations ◽  
Severe Neutropenia ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Hematopoietic Stem ◽  
Case Presentation ◽  
Neurological Abnormalities ◽  
Kostmann Syndrome ◽  
History Of

Background: Severe congenital neutropenia (SCN), also known as Kostmann syndrome, is a rare heterogeneous group of diseases characterized by arrested neutrophil maturation in the bone marrow.Case Presentation: We report a case of Kostmann syndrome and review previously reported SCN cases with neurological abnormalities. A 10-year-old boy had a history of recurrent, once a month, infection starting at 6 months of age. He had neutropenia for more than 9 years, as well as intellectual disability. He was homozygous for the exon 3 c.430dupG mutation of the HAX1 gene NM-006118. After treatment of antibiotics and G-CSF, his symtoms were relieved and was 3 months free of infection. The search revealed 29 articles related to Kostmann syndrome caused by HAX1 gene mutation; they were screened, and the main clinical features of 13 cases of Kostmann syndrome with neurological abnormalities were summarized and analyzed.Conclusions: Kostmann syndrome has three main characteristics: severe neutropenia (<0.2 × 109/L), maturation arrest of granulopoiesis at the promyelocyte stage, and death due to infections. HAX1 gene mutations affecting both isoforms A and B are associated with additional neurological symptoms. G-CSF can improve and maintain neutrophil counts, and improve prognosis and quality of life. At present, hematopoietic stem cell transplantation is the only cure.

scholarly journals Children with rare diseases of neutrophil granulocytes: from therapeutic orphans to pioneers of individualized medicine

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 33-37 ◽  
Author(s):  
Christoph Klein
Keyword(s):  
Individualized Medicine ◽  
Neutrophil Granulocytes ◽  
Basic Principles ◽  
Hematopoietic Stem ◽  
General Role ◽  
New Horizons ◽  
New Ideas ◽  
And Function ◽  
Stimulating Factor

Abstract Neutrophil granulocytes are the most abundant immune cells in the blood yet the pathways orchestrating their differentiation and biological function remain incompletely understood. Studying (ultra-) rare patients with monogenetic defects of neutrophil granulocytes may open new horizons to understand basic principles of hematopoiesis and innate immunity. Here, recent insights into genetic factors controlling myelopoiesis and their more general role in biology will be presented in a clinical perspective. Advances in supportive care, first and foremost the use of recombinant human granulocyte-colony stimulating factor, has made a substantial difference for the quality of life and life expectancy of patients with congenital neutropenia (CN). Up to date, the only definitive cure can be provided by transplantation of allogeneic hematopoietic stem cells. The elucidation of the underlying molecular factors contributing to defective differentiation and function of neutrophil granulocytes nurtures new ideas of targeted individualized therapies.

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