The Shape of µ-How Morphological Analyses Shape the Study of Microglia.

Microglia, the innate immune cells of the CNS parenchyma, serve as the first line of defense in a myriad of neurodevelopmental, neurodegenerative, and neuroinflammatory conditions. In response to the peripheral inflammation, circulating mediators, and other external signals that are produced by these conditions, microglia dynamically employ different transcriptional programs as well as morphological adaptations to maintain homeostasis. To understand these cells' function, the field has established a number of essential analysis approaches, such as gene expression, cell quantification, and morphological reconstruction. Although high-throughput approaches are becoming commonplace in regard to other types of analyses (e.g., single-cell scRNA-seq), a similar standard for morphological reconstruction has yet to be established. In this review, we offer an overview of microglial morphological analysis methods, exploring the advantages and disadvantages of each, highlighting a number of key studies, and emphasizing how morphological analysis has significantly contributed to our understanding of microglial function in the CNS parenchyma. In doing so, we advocate for the use of unbiased, automated morphological reconstruction approaches in future studies, in order to capitalize on the valuable information embedded in the cellular structures microglia inhabit.

Specification of CNS macrophage subsets occurs postnatally in defined niches.

All tissue-resident macrophages of the central nervous system (CNS)-including parenchymal microglia, as well as CNS-associated macrophages (CAMs1) such as meningeal and perivascular macrophages2-7-are part of the CNS endogenous innate immune system that acts as the first line of defence during infections or trauma2,8-10. It has been suggested that microglia and all subsets of CAMs are derived from prenatal cellular sources in the yolk sac that were defined as early erythromyeloid progenitors11-15. However, the precise ontogenetic relationships, the underlying transcriptional programs and the molecular signals that drive the development of distinct CAM subsets in situ are poorly understood. Here we show, using fate-mapping systems, single-cell profiling and cell-specific mutants, that only meningeal macrophages and microglia share a common prenatal progenitor. By contrast, perivascular macrophages originate from perinatal meningeal macrophages only after birth in an integrin-dependent manner. The establishment of perivascular macrophages critically requires the presence of arterial vascular smooth muscle cells. Together, our data reveal a precisely timed process in distinct anatomical niches for the establishment of macrophage subsets in the CNS.

The ethics of clinical applications of germline genome modification: a systematic review of reasons.

STUDY QUESTION: What are the reasons for or against the future clinical application of germline genome modification (GGM)? SUMMARY ANSWER: A total of 169 reasons were identified, including 90 reasons for and 79 reasons against future clinical application of GGM. WHAT IS KNOWN ALREADY: GGM is still unsafe and insufficiently effective for clinical purposes. However, the progress made using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)- CRISPR-associated system (Cas) has led scientists to expect to overcome the technical hurdles in the foreseeable future. This has invited a debate on the socio-ethical and legal implications and acceptability of clinical applications of GGM. However, an overview of the reasons presented in this debate is missing. STUDY DESIGN, SIZE, DURATION: MEDLINE was systematically searched for articles published between January 2011 and June 2016. Articles covering reasons for or against clinical application of intentional modification of the nuclear DNA of the germline were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two researchers independently extracted the reported reasons from the articles and grouped them into categories through content analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The systematic search yielded 1179 articles and 180 articles were included. Most papers were written by professionals in ethics, (science) journalism and biomedical sciences. Overall, 169 reasons were identified, including 90 reasons for, and 79 reasons against future clinical application of GGM. None of the included articles mentioned more than 60/169 reasons. The reasons could be categorized into: (i) quality of life of affected individuals; (ii) safety; (iii) effectiveness; (iv) existence of a clinical need or alternative; (v) costs; (vi) homo sapiens as a species (i.e. relating to effects on our species); (vii) social justice; (viii) potential for misuse; (ix) special interests exercising influence; (x) parental rights and duties; (xi) comparability to acceptable processes; (xii) rights of the unborn child; and (xiii) human life and dignity. Considerations relating to the implementation processes and regulation were reported. LIMITATIONS, REASONS FOR CAUTION: We cannot ensure completeness as reasons may have been omitted in the reviewed literature and our search was limited to MEDLINE and a 5-year time period. WIDER IMPLICATIONS OF THE FINDINGS: Besides needing (pre)clinical studies on safety and effectiveness, authors call for a sound pre-implementation process. This overview of reasons may assist a thorough evaluation of the responsible introduction of GGM. STUDY FUNDING/COMPETING INTEREST(S): University of Amsterdam, Alliance Grant of the Amsterdam Reproduction and Development Research Institute (I.D.), and Clinical Center, Department of Bioethics, National Institutes of Health Intramural Research Program (S.H.). There are no competing interests.