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Written by | Niu Chunxiao, Zou Tao Responsible editor| Wang Sizhen Edited by Summer: Hemopoietic
stem cells (HSCs).
Surrounded by a hematopoietic microenvironment called niche in mammalian fetal liver, umbilical cord blood, and bone marrow, it can produce hematopoietic precursor cells
of all lineages through self-renewal and differentiation.
Extramedullary hematopoiesis usually occurs as a pathological compensation when
the hematopoietic function of the bone marrow is disrupted or the body is not meeting the needs of the body.
In recent years, there have been several reports of in situ differentiation of tissue-resident hematopoietic precursor cells to produce tissue-resident immune cells, but the physiological extramedullary hematopoiesis of multiple lineages in adulthood has not been discovered
.
The meninges are three layers of connective tissue membranes that enclose the central nervous system, with the outer dura mater adjacent to the skull and the inner part including the arachnoid membrane and the pia mater
covering the cerebral cortex.
Recently, rapid advances in neuroimmunology have revealed the existence of a variety of immune cells in the meninges, including myeloid cells and B cells, because conjoined symbiotic mouse experiments have shown that meningeal myeloid cells and B cells are not supplemented by blood, and previous studies have found that there are ossified vascular channels between the skull bone marrow and the dura mater, and the mainstream view speculates that these meningeal immune cells are derived from the skull bone marrow [1-3], and another study refuted this hypothesis by finding that skull-labeled B cells were not present in the meninges through an improved dye-labeling method [4].
Therefore, the source of meningeal immune cells remains inconclusive
.
On November 08, 2022, Zhang Jiyan's team from the Military Medical Research Institute was in Cell Reports A research paper entitled "Identification of hematopoietic stem cells residing in the meninges of adult mice at steady state" was published online
。 In this paper, by mechanical separation of dural leukocytes, it was found that HSCs exist in the meninges of adult mice, and meningeal HSCs have tissue-specific expression profiles, which can provide white blood cells more adapted to the local microenvironment for the central nervous system.
This expands our understanding of physiological extramedullary hematopoiesis and provides a more reasonable explanation
for the source of meningeal immune cells.
In this study, the authors speculated that there were HSCs in the dura mater based on the clues provided by single-cell sequencing in the literature, and the general method of enzymatic digestion and isolation of white blood cells may damage these cells, resulting in these cells being undetected, so the researchers dissociated dural leukocytes by mechanical separation.
Flow cytometry was then performed to obtain non-blood-derived CD45+ cells for 10X single-cell transcriptome sequencing
.
In addition to finding a cell population consistent with previous reports, it was clustered into a small group of cells expressing high levels of hematopoietic precursor markers such as Kit, Cd34, Angpt1, Hlf, and Ctla2a.
To analyze this group of precursor cells in more detail, the researchers again sorted Lin-/low c-Kit+ cells from the dura, skull, and femur for single-cell sequencing and enriched them into a group of mouse HSC markers such as Procr, Esam, and Ly6a (Sca-1) were significantly enriched, while Cd34 and Cd48 were relatively deficient cells
。 Interestingly, HSCs have tissue-specific expression profiles
.
GO_BP enrichment analysis showed that dura mater and skull HSCs were more similar than femoral HSCs, "mRNA processing" and biosynthetic processes such as "cytoplasmic translation" exhibit molecular enrichment and down-regulate the "response to viruses" of transcriptions
.
It suggests that dura mater and skull HSCs are more active than femoral HSCs and perform different functions locally (Figure 1).
Figure 1: Mouse meningeal single-cell sequencing and analysis (Source: Niu, et al.
, Cell Rep, 2022).
2Phenotypic identification of mouse meningeal HSCs and their downstream precursor cells (Source: Niu, et al.
, Cell Rep, 2022).
Next, flow cytometry confirmed the presence of HSCs in mechanically isolated dural leukocytes, LSKs (Lin-/low SCA-1+c-Kit+) in dura mater, skull, and femoral leukocytes HSCs (Lin−/lowSca-1+c-Kit+CD150+CD48−) is similar, but LKs (Lin−/low SCA-1−c-Kit+) is lowest in the dura mater and highest
in the femur.
Because the total number of meningeal leukocytes is small, the number of LKs, LKs and HSCs in the dura mater is significantly lower than that of the femur and skull.
Immunofluorescence analysis showed the presence of extravascular CD150+Lin/CD48−/low cells in the dura mater, most of which were distributed
along the sinus.
In addition, dura mater and skull HSCs expressed a higher proportion of the cell division marker Ki67, indicating that they were indeed more active than femoral HSCs (Figure 2)
。 Consistent with the authors' pre-assumptions, enzymatic digestion of meningeal leukocytes would cause LKs and HSCs to disappear (Figure 3).
The study of meningeal HSCs function is mainly through colony formation and transplantation experiments, which are an effective in vitro method to assess the number and function of HSCs and their downstream precursor cells, while multi-lineage reconstruction and self-renewal ability is widely recognized as HSCs The most important features
.
The experimental results showed that the ability of skull and dural leukocytes to generate pre-B colonies in vitro was similar to that of femoral leukocytes, but the number of myeloid colonies produced was small
.
Both short-term (8 weeks) and long-term (20 weeks) first-generation transplantation experiments and second-generation transplantation experiments showed Dural HSCs do have long-term, multi-lineage hematopoietic reconstruction and self-renewal capabilities (Figure 4).
Figure 3: Different effects of enzymatic digestion and mechanical separation on meningeal HSCs (Source: Niu, et al.
, Cell Rep, 2022) Figure 4:
Functional identification of mouse meningeal HSCs and their downstream precursor cells (Source: Niu, et al.
, Cell Rep, 2022)
Figure 5: The occurrence, development and local maintenance mechanism of the meningeal hematopoietic microenvironment in mice (Source: Niu, et al.
, Cell Rep, 2022),
further, the authors explore the genesis and development of the meningeal hematopoietic microenvironment, revealing HSCs in mice after birth by flow cytometry Colonization of the skull bone marrow cavity occurs at 1 to 7 days, while most colonization of dural HSCs occurs after
7 days of life.
The results of immunofluorescence are consistent with
this.
By sequencing the whole transcriptome of the neonatal murine dura mater, it was found that the meninges expressed all the niche molecules required for bone marrow hematopoiesis one day after birth, and the expression of some molecules increased further 1-2 weeks after birth
.
To explore the mechanism of local maintenance of meningeal HSCs, the authors successfully constructed WT/GFP and CD45.
1/CD45.
2 conjoined symbiotic mice by surgery, indicating that under homeostasis conditions, symbiotic mice are intermediate HSCs are not substantially exchanged
.
But the WT mice were irradiated at a low dose of 3Gy while the conjoined GFP mice were protected with lead bricks, and flow cytometry showed WT The proportion of GFP+ cells in HSCs everywhere in mice increased, indicating that bloodborne supplementation was increased
.
Radiation not only causes a decrease in HSCs, but also leads to increased vascular permeability, and to determine the effect of vascular permeability on the bloodsource supplementation of meningeal HSCs, the researchers wrote in CD45.
2 Experimental autoimmune encephalomyelitis (EAE) was induced in female conjoined mice, however hematogenous supplementation of meningeal HSCs did not increase in the presence of significant leakage of brain parenchyma and meningeal vessels in model mice (Figure 5).
。 Therefore, the maintenance of adult murine meningeal HSCs is dependent on the local microenvironment and increases bloodborne supplementation only when the number
decreases.
Figure 6 The presence of HSCs in the meninges of adult mice can provide the central nervous system with white blood cells more adapted to the local microenvironment (Source: Niu , et al.
, Cell Rep, 2022)
article conclusion and discussion, inspiration and prospects In summary, the study revealed the presence of HSCs in the meninges of steady-state adult mice, these HSCs Mice colonize approximately 7 to 14 days after birth, exhibit specific transcription profiles, and have the ability to reconstruct and self-renew multiple lineages, which are replenished from the blood only when their local numbers decrease (Figure 6).
This paper provides new ideas
for the study of the immune microenvironment of the central nervous system.
However, it is worth noting that the study did not explore the presence of HSCs in the human meninges, nor did it clarify the possible role
of the "skull-dura mater channel" in the implantation and local maintenance of meningeal HSCs.
For tissue-specific HSCs expression profiles, it is unclear whether specific HSCs are implanted into the skull and meninges, or whether the same HSCs are implanted in different sites, but the local expression profiles are gradually changed
by the microenvironment.
The spatial localization and interaction between meningeal niche molecules expressing cells and HSCs also need to be analyzed
.
Original link: https://pubmed.
ncbi.
nlm.
nih.
gov/36351383/
.
Professor Zhang Jiyan is also a dual-appointment researcher
at the Beijing Center for Brain Science and Brain-like Research.
The research was supported by a grant
from the National Natural Science Foundation of China (81930027, 92169207, 81625010).
The team recruits formal civilian personnel, requires a degree: doctorate, consult Mr.
Cao for details, caojunxia1234@163.
com have a neurobiological background
.
First authors: Niu Chunxiao (first from left), Yu Jijun (second from left), Zou Tao (first from right); Corresponding author: Zhang Jiyan (second from right) (photo courtesy of Zhang Jiyan's team).
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Skull and vertebral bone marrow are myeloid cell reservoirs from the meninges and CNS parenchyma.
Science.
2021.
373: eabf7844.
[2] Brioschi S, et al.
Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders.
Science.
2021.
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[3] Wang Y, et al.
Early developing B cells undergo negative selection by central nervous system-specific antigens in the meninges.
Immunity.
2021.
54: 1–11.
[4] Schafflick D, et al.
Single-cell profiling of CNS border compartment leukocytes reveals that B cells and their progenitors reside in non-diseased meninges.
Nat.
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24: 1225–1234.
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