doi: 10.1038/s41586-019-1104-8.
Epub 2019 Apr 10.
The bone marrow microenvironment at single-cell resolution
Affiliations
- PMID: 30971824
- PMCID: PMC6607432
- DOI: 10.1038/s41586-019-1104-8
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The bone marrow microenvironment at single-cell resolution
Nature.
2019 May.
Erratum in
-
Author Correction: The bone marrow microenvironment at single-cell resolution.Nature. 2019 Aug;572(7767):E6. doi: 10.1038/s41586-019-1394-x. Nature. 2019. PMID: 31296938
Abstract
The bone marrow microenvironment has a key role in regulating haematopoiesis, but its molecular complexity and response to stress are incompletely understood. Here we map the transcriptional landscape of mouse bone marrow vascular, perivascular and osteoblast cell populations at single-cell resolution, both at homeostasis and under conditions of stress-induced haematopoiesis. This analysis revealed previously unappreciated levels of cellular heterogeneity within the bone marrow niche and resolved cellular sources of pro-haematopoietic growth factors, chemokines and membrane-bound ligands. Our studies demonstrate a considerable transcriptional remodelling of niche elements under stress conditions, including an adipocytic skewing of perivascular cells. Among the stress-induced changes, we observed that vascular Notch delta-like ligands (encoded by Dll1 and Dll4) were downregulated. In the absence of vascular Dll4, haematopoietic stem cells prematurely induced a myeloid transcriptional program. These findings refine our understanding of the cellular architecture of the bone marrow niche, reveal a dynamic and heterogeneous molecular landscape that is highly sensitive to stress and illustrate the utility of single-cell transcriptomic data in evaluating the regulation of haematopoiesis by discrete niche populations.
Conflict of interest statement
Figures
RNA-seq analysis of the bone marrow microenvironment
populations. a, Representative two-photon imaging of
tdTomato+ vascular cells
(VE-Cad—tdTomato+), perivascular cells
(LEPR—tdTomato+) and osteoblasts
(COL2.3—tdTomato+). b, Representative
flow cytometry of VE-Cad-tdTomato+, LEPR-tdTomato+ and
COL2.3-tdTomato+ populations. c, Principal
component analysis of vascular (VE-Cad-tdTomato+,
n = 4) (red), perivascular LEPR+
(LEPR-tdTomato+, n = 4) (purple) and
osteoblast (COL2.3-tdTomato+, n = 4) (blue)
populations, based on the expression of the 1,000 most-variable genes in
bulk RNA-seq. d, Relative expression levels of
COL2.3+, LEPR+and VE-Cad+ signature
genes across the three subpopulations of the bone marrow niche in bulk
RNA-seq. Normalization and statistical analysis were performed using the
DESeq2 R package. e, Normalized expression levels of the
population-specific markers VE-Cad (Cdh5), LEPR
(Lepr) and COL2.3 (Col1a1) for all
scRNA-seq clusters. n = 9,622 cells. The data are mean
± s.e.m. Experiments were repeated independently on more than 10
(a, b) biological samples with similar results.
Analysis of VE-Cad+, LEPR+ and
COL2.3+populations. a, Schematic workflow of independent and integrated
analysis of VE-Cad+, LEPR+ and COL2.3+
scRNA-seq data. b, t-SNE representation of
VE-Cad+ populations only. Cluster C1 corresponds to arterial
cluster V1 (Ly6ahigh). Cluster C2 corresponds to
sinusoidal cluster V2 (Stab2high). Cluster C3 is
the cycling cluster. c, Normalized expression of arterial,
sinusoidal and cycling markers (Ly6a, Stab2 and
Mki67, respectively) (n = 4,551
cells). d, Gene signatures of VE-Cad+subpopulations
in the bone marrow, based on the relative expression levels of the ten
most-significant markers for each cluster. e,
t-SNE representation of the LEPR+ population
only. Cluster C1 corresponds to the adipocytic-primed cluster P1
(Mgphigh) and encompasses cluster P2.
Cluster C2 corresponds to P3 (Wif1high), and C3
to P4 (Spp1high). f, Normalized
expression of P1, P3 and P4 markers (Mgp, Wif1 and
Spp1, respectively). n = 3,907 cells.
g, Gene signatures of LEPR+subpopulations in the
bone marrow, based on the relative expression levels of the ten
most-significant markers for each cluster. h,
t-SNE representation of the COL2.3+
population only. Cluster C1 corresponds to cluster O1
(Col16a1high), cluster C2 to O2
(Fbn1high) and C3 to O3
(Bglaphigh). i, Normalized
expression of O1, O2 and O3 markers (Col16a1, Fbn1 and
Bglap, respectively). n = 1,114 cells.
j, Gene signatures of COL2.3+ subpopulations in
the bone marrow, based on the relative expression levels of the ten
most-significant markers for each cluster. Cluster C4 represents arterial
vascular cells (Cdh5, Kdr and Ly6e); C5 is
glial-like cells (Fabp7, Mpz and Endrb);
and C6 is myocyte-like cells (Pgf, Pln and
Acta2). The data shown in c, f, i are mean
± s.e.m. MAST with Bonferroni correction (d, g, j).
Characterization of VE-Cad+ subpopulations. a, Relative average scRNA-seq expression levels of the
previously described arterial and sinusoidal gene signatures at a steady
state, within the VE-Cad+ clusters V1 and V2. b,
Average scRNA-seq expression levels (left) (n = 4,669
cells) and bone marrow immunofluorescence (right) of arterial expression of
SCA-1 (Ly6a), CD102 (Icam2) and PODXL
(Podxl) (n = 3 mice); LAMA1 staining
(blue) labels all bone vessels; yellow arrowheads indicate arterial vessels.
Dashed lines mark bone marrow (bm), compact bone (cb), growth plate (gp) and
metaphyseal (mp) bone regions. c, Bone marrow
immunofluorescence of arterioles co-stained with SCA-1 and PODXL.
n = 3 mice. d, Average scRNA-seq
expression levels (left) and bone marrow immunofluorescence (right) of
sinusoidal VEGFR3 (Flt4) (red) and CD54
(Icam1) (green) markers. n = 3 mice.
LAMA1 staining (blue) labels all bone vessels. e, Average
scRNA-seq expression levels and representative flow cytometry analysis of
the arterial subpopulation (V1) using SCA-1 and scRNA-seq-identified LY6C
(Ly6c1) and CD34 (Cd34) from
VE-Cad–tdTomato bone marrow (n = 3 mice). Cells were
pre-gated on DAPI−tdTomatohigh cells. The data
in b, d, eare mean ± s.e.m.
Characterization of perivascular LepR+
subpopulations. a, Relative average scRNA-seq expression levels of the
adipocytic(Hp, Lpl, Adipoq, Slc1a5, Cd302, Gas6 and
Apoe) and osteo-associated (Ibsp, Spp1, Alpl,
Wif1, Bglap, Sp7 and Runx2)genes, as well as
markers used for characterization of LEPR+ cell (Esm1,
Vcam1, Cd200 and Cd63). b, ESM1
(green) bone marrow immunofluorescence of LEPR-tdTomato femur. LAMA1
staining (blue) labels all bone vessels. Yellow arrowhead,
LEPR+ESM1+ cells; white arrowheads indicate
LEPR+ESM1− cells. c, CD200
(green) and CD63 (red) bone marrow immunofluorescence of LEPR-tdTomato
femur. Nuclei, DAPI (blue). Yellow arrowhead, LEPR+,
CD200+, CD63+ cells; white arrowhead,
LEPR+, CD200−, CD63−
cells. d Human mesenchymal stem cell (hMSC) gene signature
module score, overlaid on t-SNE representation
(n=9,622 cells). e, Flow cytometry
representation of VCAM1highCD63low and
VCAM1lowCd63high cells of tdTomato+
subpopulations in LEPR-tdT bone marrow. Cells were pre-gated on
DAPI− tdTomatohigh cells. f,
Fibroblastic colony-forming unit activity of sorted total LEPR+
(purple), LEPR+VCAM1lowCD63high (maroon),
and LEPR+VCAM1highCD63low (yellow) cells
from bone marrow of LEPR-tdTomato mice (n=8).The data are
mean ± s.d. (f). N.S., not significant,
*P ≤ 0.05, **P ≤ 0.01,
***P ≤ 0.001 (Student’
t-test, two-tailed (f). Data are
representative of two (b, c) or three (e, f)
independent experiments.
Characterization of Col2.3+ subpopulations and cycling
cells. a, Relative average scRNA-seq expression levels of O1
(Edil3, Mmp14, Ostn, Col121, Angptl2 and
Col16a1), O2- (Sox9, Comp, Chad and
Col10a1), and O3- (Col11a2, Col1a2, Sparc,
Bglap2 and Bglap3) associated genes.
b-d, Average scRNA-seq expression levels
(n = 9,622 cells) and bone marrow immunofluorescence of
MMP14 (green) (b) (n = 3 mice), CD9 (green)
(c) (n = 3 mice) and CAR3 (green)
(d) (n = 3 mice) in Col2.3-tdTomato femur,
with arrows indicating co-staining with tdTomato (red). Nuclei, DAPI (blue).
Arrowhead, Col2.3+MMP14+ (b),
COL2.3+CD9+ (c), and
COL2.3+CAR3+ (d). e,
Expression levels of Mki67 in all identified subpopulations
(n = 9,622 cells). f, Enriched Gene
ontology biological processes terms most-strongly associated with cycling
cluster (C), color-coded by significance of enrichment and size on the basis
of the fraction of overlapping genes. n = 9,622 cells.
g, Contribution of VE-cad-tdTomato+,
LEPR-tdTomato+, and COL2.3-tdTomato+ cells to the
cycling cluster (C) at steady state n = 70 cells. The data
b-e are mean ± s.e.m
Effect of treatment with 5-FU on subsets of the bone marrow
niche. a, Representative hematoxylin and eosin-stained
sections of BM on day 5 following control or 5-FU treatment
(n = 3 animals). b, Frequency and numbers
of BM LSK cells on day 5 following control (CNTRL) (n = 4)
or 5-FU treatment (n = 5). c, Absolute numbers
of BM niche cells, vascular VEcad+ (CNTRL: n =
4; 5-FU: n = 10), perivascular LepR+ (CNTRL:
n = 2; 5-FU: n = 5), and
Col2.3+ osteoblasts (CNTRL: n = 4; 5-FU:
n = 5) from control (PBS) and 5-FU treated animals.
d, Gene signatures of niche LepR+
sub-populations, including cluster P5, based on the average relative
expression levels of the 10 most significant markers for each cluster
exclusively within the LepR+ subset. MAST with Bonferroni
correction. e, Relative expression levels of upregulated
adipogenesis-associated genes and downregulated osteogenesis-associated
genes in LepR+ subpopulations in response to 5-FU treatment.
f, LepR+ cells enriched pathways in response to
5-FU treatment (n = 17,374 cells). Fisher exact test.
g, Contribution of VEcad-tdT+,
Lepr-tdT+, and Col2.3-tdT+ cells to cycling
cluster (C) following 5-FU treatment (n = 418 cells).
h, Expression levels of Mki67 in all
identified subpopulations at steady state and following 5-FU
(n = 17,374 cells). Data are mean ± s.d.
*P ≤ 0.05, **P ≤ 0.01,
***P ≤ 0.001 (Student’s
t-test, two-tailed) (b-c). The data
(h) are mean ± standard error.
a, b, Heat map and hierarchical clustering of mean
normalized expression values of VE-Cad+ (a) and
LEPR+ (b) control-treated and 5-FU-treated
samples for 5-FU-modulated genes (top 50 differentially expressed) in two
independent scRNA-seq experiments. c, d, log-transformed fold
changes of differentially expressed genes (up- and downregulated >
1.2×, adjusted P value < 0.001) in
5-FU-treated versus control-treated VE-Cad+ (n =
697 genes) cells (c) and LEPR+ (n =
829 genes) cells (d), for two independent experiments. The
trend line (dashed) and the confidence interval (grey shading) were
calculated using the linear model. MAST with Bonferroni correction.
VE-Cad+ control-treated, n = 5,796 cells;
VE-Cad+ 5-FU-treated, n = 1,481 cells;
LEPR+ control-treated, n = 6,128 cells;
LEPR+ 5-FU-treated, n = 4,867 cells.
a, Reverse-transcription PCR of Dll4,
Dll1 and Jag1 in vascular cells (red),
perivascular LEPR+ cells (purple) and osteoblasts (blue),
normalized to Gapdh (n = 4 mice).
b, Low-magnification immunofluorescence images of thymus
sections from Dll4-mCherry, Dll1-mCherry and
Jag1-mCherry mice. c, Representative flow
cytometry, measuring mCherry fluorescence in total bone marrow of
Dll4-mCherry, Dll1-mCherry and
JAG1-mCherry mice. Indicated values represent
percentages of the complete CD144+ and
mCherry+CD144− populations. Cells were
pre-gated on DAPI− cells. d, Representative
mCherry levels in
DAPI−CD45lowTER119lowCD144+
bone marrow endothelial cells from Dll4-mCherry (red)
(n = 4), Dll1-mCherry(blue)
(n = 3), Jag1-mCherry (black)
(n = 4) and control (grey) (n = 5)
mice. e, f, Representative immunofluorescence metaphysis and
diaphysis of Dll4-mCherry (e) and
Dll1-mCherry (f) bone marrow
(n = 3 mice). mCherry (red) and LAMA1 (blue). g,
h, Representative two-photon images of bone marrow from intact
(left) or dextran-injected (right)
Dll4-mCherry(g) and
Dll1-mCherry (h) mice (n
= 3 mice). i, Normalized counts of key differentially expressed
genes from bulk RNA-seq performed on
CD144−DLL1+ cells (purple) (from
n = 2 mice) and CD144+DLL1+ cells
(black) (from n = 2 mice). j, Representative
flow cytometry histogram measuring mCherry fluorescence in NK1.1+
population from Dll1-mCherry (pink) and control (black)
mice (n = 3 mice). The data are mean ± s.d. N.S.,
not significant, *P ≤ 0.05, **P
≤ 0.01, ***P ≤ 0.001, Student’s
t-test, two-tailed. Data are representative of two
(a, e–h, j) or three (b–d) independent
experiments.
a, b, Representative percentage of bone marrow
progenitors in VE-CadcreER-Dll4i3COIN
and littermate-control mice for common lymphoid progenitors gate (CLP gate)
(control, n = 10;
VE-CadcreER-Dll4i3COIN,
n = 11) (a) and granulocyte–monocyte progenitors gate
(GMP gate) (control, n = 10;
VE-CadcreER-Dll4i3COIN,
n = 13) (b). c, Frequencies
of CD3+ T cells (control, n = 12;
VE-CadcreER-Dll4i3COIN,
n = 11). d, Total numbers of mature
haematopoietic subsets in tamoxifen-treated
VE-CadcreER-Dll4i3COIN and
littermate-control mice, including B220+ B cells (control,
n = 10;
VE-CadcreER-Dll4i3COIN,
n = 10), CD3+ T cells (control,
n = 10;
VE-CadcreER-Dll4i3COIN,
n = 10) and CD11b+GR1+ myeloid
cells (control, n = 10;
VE-CadcreER-Dll4i3COIN,
n = 10). e, Absolute numbers of thymocytes
from VE-CadcreER-Dll4i3COIN mice
(n = 11) and littermate-control mice
(n = 9). f, Representative flow cytometry
analysis of thymic subsets in tamoxifen-treated
VE-CadcreER-Dll4i3COIN and
littermate-control mice. g, Frequencies (control,
n = 8;
VE-CadcreER-Dll4i3COIN,
n = 5) and absolute numbers (control,
n = 6;
VE-CadcreER-Dll4i3COIN,
n = 4) of early thymic progenitors in thymi from
VE-CadcreER-Dll4i3COIN and
littermate-control mice. h, Percentage (control,
n = 10;
VE-CadcreER-Dll4i3COIN,
n = 10) of HSCs, MPP2 cells, MPP3–4 cells, MPP4 cells
and LSK cells from the bone marrow of
VE-CadcreER-Dll4i3COIN and
littermate-control mice. i, Total numbers of bone marrow HSCs,
MPP2 cells, MPP3 cells, MPP4 cells and LSK cells from
VE-CadcreER-Dll4i3COIN and
littermate-control mice (control, n = 10;
VE-CadcreER-Dll4i3COIN,
n = 10). j, Representative
immunofluorescence of early progenitors
(Lin−CD48−CD150+) adjacent to the
DLL4-producing vascular endothelium in Dll4-mCherry. Lin
cocktail, CD11b, GR1, CD41, TER119 and B220. Arrowhead,
Lin−CD150+ progenitors. n = 3
mice. k, scRNA-seq t-SNE visualization of the
LSK compartment (n = 21,116 cells), colour-coded by
genotype. l, m, Distribution of enrichment scores for myeloid
progenitor (l) and HSC (m) gene signatures within
the scRNA-seq-profiled HSPC populations from bone marrow of
tamoxifen-treated
VE-CadcreER-Dll4i3COIN mice
(pooled n = 2) and littermate-control mice (pooled
n = 2). n = 21,116 cells. The data are
mean ± s.d. NS, not significant, *P ≤ 0.05,
**P ≤ 0.01, ***P ≤
0.001, Student’s t-test, two-tailed (a–d,
g–i) or Wilcoxon rank-sum test (l, m). Data are
representative of four (a–e) or two (g)
independent experiments.
a–f, Flow cytometry analysis of bone marrow progenitors
in VE-Cad-Dll1fl/fl and littermate-control mice,
showing equivalent frequencies of common lymphoid progenitors (control,
n = 10; VE-Cad-Dll1fl/fl,
n = 8) (a), granulocyte–monocyte
progenitors (control, n = 7;
VE-Cad-Dll1fl/fl, n =
9) (b) and MPP4 cells (control, n = 10;
VE-Cad-Dll1fl/fl, n =
10) (c), of B220+ B cells (control,
n = 10; VE-Cad-Dll1fl/fl,
n = 10) (d, f), CD3+ T cells
(control, n = 10;
VE-Cad-Dll1fl/fl, n = 10)
(d, f) and CD11b+GR1+
monocytic–granulocytic subset (control, n = 8;
VE-Cad-Dll1fl/fl, n =
9) (e, f). g, Absolute numbers of thymocytes from
VE-Cad-Dll1fl/fl and littermate-control
mice (control, n = 6;
VE-Cad-Dll1fl/fl, n = 10).
h, Representative flow cytometry analysis of thymic subsets
in VE-Cad-Dll1fl/fl and littermate-control mice.
i, Frequencies (control, n = 4;
VE-Cad-Dll1fl/fl, n =
6) and absolute numbers (control, n = 4;
VE-Cad-Dll1fl/fl, n =
6) of early thymic progenitors from thymi of
VE-Cad-Dll1fl/fl and littermate-control
mice. The data are mean ± s.d. N.S., not significant,
Student’s t-test, two-tailed. Data are
representative of three independent experiments.
a, Schematic representation of BM niche: osteoblasts
(Col2.3+, blue), perivascular LepR+ (LepR+,
purple), and vascular cells (VEcad+, red). b. Expression
levels of genes associated with niche-specific Cre strains, including
Cdh5 (VE-cadherin), Lepr (Leptin receptor)
and Col1a1 (Col2.3) overlaid on tSNE representation
(n=9,622 cells). Dashed lines generally encompass the cells
profiled in Col2.3+, LepR+, VEcad+ libraries.
c, Gene signatures of VEcad+, LepR+, and
Col2.3+ sub-populations based on the relative expression levels
of the 10 most significant markers for each of the 10 clusters, displaying 100
randomly-selected cells per cluster. MAST with Bonferroni correction.
d, tSNE visualization of color-coded clustering of BM niche
(n=17,374 cells). Dashed lines generally encompass the
examined VEcad+ (red), LepR+ (purple), Col2.3+
(blue) BM niche populations and the cycling cells (sea green).
a-c, Gene signatures of BM niche sub-populations based on
the average relative expression levels of the 10 most significant markers for
each cluster exclusively within the parent niche subsets (VEcad+
(a), LepR+(b), or
Col2.3+(c)) at steady state. MAST with Bonferroni
correction. d, Reconstructed cell differentiation trajectory of
LepR+ and Col2.3+ clusters colored by subpopulation
identity. e, Expression levels of indicated genes in
LepR+ and Col2.3+ cells with respect to their
pseudotime coordinates. Black lines depict the LOESS fit of the normalized
expression values. f, Expression levels of pro-hematopoietic
factors in the non-cycling clusters (n=9,622 cells). The data
are mean ± standard error.
a, VEcad+ (red), LepR+ (purple), and
Col2.3+ (blue) cells at steady state (dark) or following 5-FU
treatment (light) overlaid on tSNE representation (n=17,374
cells). b, tSNE plot of color-coded clusters of all examined
(control and 5-FU treated) BM niche cells (n=17,374 cells).
Dashed lines generally encompass the examined VEcad+ (red),
LepR+(purple), Col2.3+ (blue) BM niche populations and
the cycling cells (sea green). c, Frequencies of each
sub-population within VEcad+, LepR+, and
Col2.3+ compartments under the indicated condition.
d, Relative expression of pro-hematopoietic factors examined in
Fig. 2e in response to 5-FU treatment
(n=17,374 cells). Adjusted *P≤
0.05, **P≤ 0.01, ***P< 0.001
(MAST with Bonferroni correction). The data are mean ± standard
error.
a, Map of BAC clones used to drive transgenes
mDll4-mCherry, mDll1-mCherry, and
mJag1-mCherry. b, Representative flow
cytometry histogram measuring mCherry fluorescence in
DAPI−CD45/Ter119lowCD144+
endothelial cells from BM of mDll4-mCherry,
mDll1-mCherry, and mJAG1-mCherry.
Indicated values represent percentages of the complete CD45/Ter119 population.
c-d, Representative two photon images of BM from
dextran-injected mDll4-mCherry (c) and
mDll1-mCherry (d). (c-d) Scale
bars are 100 μm and 25 μm, as indicated in the images. Data are
representative of three independent experiments (b-d).
a-c, Representative flow cytometry (a,b) and
frequencies (c) of mature hematopoietic subsets in
VEc-Dll4i3COIN and littermate control animals,
including B220+ B cells (CNTRL: n=12;
VEc-Dll4i3COIN: n=11) and
CD11b+Gr1+ cells (CNTRL: n=12;
VEc-Dll4i3COIN: n=11).
d, LSK compartment scRNA-seq tSNE visualization
(n=21,116 cells), color-coded by the identified HSPC
populations. e, Log-transformed normalized expression levels of
myeloid-associated genes (Calr, Ctsg,
Elane, and Mpo) and Mki67
across HSPC populations in control and
VEc-Dll4i3COIN LSK cells
(n=21,116 cells). Violin plots depict kernel density estimation
to show the distribution of expression values. Data are mean ± s.d.
*P≤ 0.05, **P≤ 0.01,
***P≤ 0.001 (Student t-test, two-tailed
(c), MAST test with Bonferroni correction (e)).
Data are representative of four (a-c) independent experiments.
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