Origin, molecular specification, and stemness of astrocytes

Abstract

Astrocytes are the most abundant cell type in the central nervous system, carrying out a wide spectrum of biological functions. During early development, neural progenitor cells in the ventricular zone first produce neurons, followed by macroglia in the form of astrocytes or oligodendrocytes. Although the lineage progression of oligodendrocytes has been well understood, the developmental staging of astrocytes has not been defined and the molecular mechanisms underlying their fate specification and differentiation remain largely unknown. The recent advent of sophisticated molecular biology technology, especially single‐cell sequencing, has enabled a deeper understanding of the patterning and molecular specification of astrocyte lineage. Based on the recent single‐cell sequencing data, we provide an up‐to‐date and mechanistic review of the early development and heterogeneity of astrocyte lineage in the developing cortex, and compile a list of stage‐specific markers for astrocyte development. In addition, emerging evidence suggests that under physiological conditions, mature astrocytes are partially specialized progenitor cells that have functionally adapted to local neuronal microenvironment. Under pathological or injury conditions, astrocytes are capable of reentering cell cycles and differentiating into other neural cell types under the influence of both intrinsic factors and environmental cues.

Utilization of ethanolamine phosphate phospholyase as a unique astrocytic marker

“…Although the expression of ETNPPL was very weak in P4 in general, an exception was observed in the ventricular and subventricular zones ( Figure 4 and Table 2 ). Since these zones are well-known neurogenic/gliogenic niches ( Luskin, 1998 ; Zheng et al, 2022 ), ETNPPL-expressing cells in these zones might not be astrocytes, although we confirmed the astrocyte-selective expression of ETNPPL in the cerebral cortex ( Figure 8 ) or spinal cord ( Supplementary Figure 10 ) in adults. A recent study found that ETNPPL + cells express the neural stem cell (NSC) marker (SOX2) or a neural progenitor cell marker (neurogenic differentiation 1), as well as a proliferation marker (proliferating cell nuclear antigen) in the adult hippocampus in primates but not in rodents ( Wang et al, 2022 ).…”

Immunological Markers for Central Nervous System Glia

“…Based on the similar gene expression profiling among RGCs, APCs, and astrocytes, we recently hypothesized that astrocytes are the resting neural precursor cells without undergoing terminal differentiation and cell-cycle exit, providing structural and metabolic support for local neurons [ 22 ]. Functional adaptions to the local neuronal milieu may explain the heterogeneity of astrocytes in the CNS.…”

“…Therefore, unlike the development of oligodendrocytes, there are few definite stage-specific molecular markers for the astrocyte lineage, and transcription factors that control the differentiation and maturation of astrocytes have yet to be found. Based on these and other findings, we propose that astrocytes are dormant neural progenitor cells that are influenced by local environments and are functionally adapted to support the local neuronal populations [ 22 ].…”

Endolysosomal dysfunction in radial glia progenitor cells leads to defective cerebral angiogenesis and compromised Blood-Brain Barrier integrity

“…Astrocytes also arise from RGCs 34 . To evaluate whether astrogenesis is also impaired in scarb2a mutants, we imaged Tg(slc1a3b:MYRGFP-2A-H2AmCherry) embryos that express the membrane-bound myristoyl-GFP (myrGFP) and the nuclear marker H2AmCherry under the control of slc1a2b/Glast promoter, a well-established astrocyte marker 35 .…”