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Arterioles and sinusoids of the bone marrow (BM) are accompanied by stromal cells that express nerve/glial antigen 2 (NG2) and leptin receptor (LepR), and constitute specialized niches that regulate quiescence and proliferation of haematopoietic stem cells (HSCs). However, how niche cells differentially regulate HSC functions remains unknown. Here, we show that the effects of cytokines regulating HSC functions are dependent on the producing cell sources. Deletion of chemokine C-X-C motif ligand 12 (Cxcl12) or stem cell factor (Scf) from all perivascular cells marked by nestin-GFP dramatically depleted BM HSCs. Selective Cxcl12 deletion from arteriolar NG2 + cells, but not from sinusoidal LepR + cells, caused HSC reductions and altered HSC localization in BM. By contrast, deletion of Scf in LepR + cells, but not NG2 + cells, led to reductions in BM HSC numbers. These results uncover distinct contributions of cytokines derived from perivascular cells in separate vascular niches to HSC maintenance. Asada  et al.  examine differential effects of CXCL12 and SCF expression by perivascular bone marrow niche cells, such as arteriolar NG2 + vascular smooth muscle cells and sinusoidal LepR + cells, on haematopoietic stem cell maintenance and mobilization.

Cell cycle quiescence is a critical feature contributing to haematopoietic stem cell (HSC) maintenance. Although various candidate stromal cells have been identified as potential HSC niches, the spatial localization of quiescent HSCs in the bone marrow remains unclear. Here, using a novel approach that combines whole-mount confocal immunofluorescence imaging techniques and computational modelling to analyse significant three-dimensional associations in the mouse bone marrow among vascular structures, stromal cells and HSCs, we show that quiescent HSCs associate specifically with small arterioles that are preferentially found in endosteal bone marrow. These arterioles are ensheathed exclusively by rare NG2 (also known as CSPG4) + pericytes, distinct from sinusoid-associated leptin receptor (LEPR) + cells. Pharmacological or genetic activation of the HSC cell cycle alters the distribution of HSCs from NG2 + periarteriolar niches to LEPR + perisinusoidal niches. Conditional depletion of NG2 + cells induces HSC cycling and reduces functional long-term repopulating HSCs in the bone marrow. These results thus indicate that arteriolar niches are indispensable for maintaining HSC quiescence. Immunofluorescence imaging and computational modelling are used to study the spatial distribution of different cell types within the haematopoietic stem cell (HSC) niche; findings show that quiescent HSCs associate specifically with small arterioles that are preferentially found in the endosteal bone marrow and are essential in maintaining this quiescence. Haematopoietic stem cell niche characterized Paul Frenette and colleagues used whole-mount confocal immunofluorescence imaging and computational modelling to study the spatial distribution of different cell types within the hematopoietic stem cell (HSC) niche. They found that quiescent HSCs associate specifically with small arterioles that are preferentially found in endosteal bone marrow and that these arterioles are essential in maintaining HSC quiescence. These results thus suggest that distinct HSC niches, quiescent or proliferative, are conferred by distinct blood vessel types.

Many chemotherapy drugs cause sensory nerve damage as well as long-lasting damage to hematopoietic regeneration in the bone marrow. Paul Frenette and his colleagues show that this hematopoietic damage is caused by injury to bone marrow sympathetic nerve fibers, disrupting the hematopoietic stem cell niche. These findings point to the potential of neuroprotective agents in preserving hematopoietic function in chemotherapy-treated patients with cancer. Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury.

Cancer stem cells (CSCs) possess the capacity for self-renewal and the potential to differentiate into non-CSCs. The recent discoveries of dynamic equilibrium between CSCs and non-CSCs revealed the significance of acquiring CSC-like properties in non-CSCs as an important process in progression of cancer. The mechanism underlying acquisition of CSC-like properties has mainly been investigated in the context of epithelial–mesenchymal transition. Here, we demonstrate the dedifferentiation process may be an alternative mechanism in acquisition of CSC-like properties in human colorectal cancer cells. By exploring the single-cell gene expression analysis of organoids developed from CD44 + CSCs, we identified TWIST1 as a key molecule for maintaining the undifferentiated state of cancer cells. Consistent with the finding, we found that TGF-beta signaling pathway, a regulator of TWIST1, was specifically activated in the undifferentiated CD44 + CSCs in human colorectal cancer using microarray-based gene expression analysis and quantitative pathology imaging system. Furthermore, we showed that external stimulation with TGF-beta and the induction of TWIST1 converted CD44 − non-CSCs into the undifferentiated CD44 + CSCs, leading to the significant increment of CSCs in xenograft models. This study strongly suggests dedifferentiation driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer.

Metabolic alterations, especially in the mitochondria, play important roles in several kinds of cancers, including acute myeloid leukemia (AML). However, AML‐specific molecular mechanisms that regulate mitochondrial dynamics remain elusive. Through the metabolite screening comparing CD34+ AML cells and healthy hematopoietic stem/progenitor cells, we identified enhanced lysophosphatidic acid (LPA) synthesis activity in AML. LPA is synthesized from glycerol‐3‐phosphate by glycerol‐3‐phosphate acyltransferases (GPATs), rate‐limiting enzymes of the LPA synthesis pathway. Among the four isozymes of GPATs, glycerol‐3‐phosphate acyltransferases, mitochondrial (GPAM) was highly expressed in AML cells, and the inhibition of LPA synthesis by silencing GPAM or FSG67 (a GPAM‐inhibitor) significantly impaired AML propagation through the induction of mitochondrial fission, resulting in the suppression of oxidative phosphorylation and the elevation of reactive oxygen species. Notably, inhibition of this metabolic synthesis pathway by FSG67 administration did not affect normal human hematopoiesis in vivo. Therefore, the GPAM‐mediated LPA synthesis pathway from G3P represents a critical metabolic mechanism that specifically regulates mitochondrial dynamics in human AML, and GPAM is a promising potential therapeutic target. The Glycerol‐3‐phosphate acyltransferases, mitochondrial (GPAM)‐mediated lysophosphatidic acid synthesis pathway regulates mitochondrial dynamics and metabolism in human acute myeloid leukemia (AML) cells. GPAM represents a specific therapeutic target for AML without affecting normal hematopoiesis.

Chow et al . report a crucial role for macrophages in erythroblast development in mice. Under conditions that induce new red blood cell formation, macrophage depletion impaired red blood cell recovery. Conversely, macrophage depletion normalized red blood cell counts in a mouse model of polycythemia vera, pointing to a potential new therapeutic strategy for this disease. Findings similar to these are reported in an accompanying paper by Ramos et al . A role for macrophages in erythropoiesis was suggested several decades ago when erythroblastic islands in the bone marrow, composed of a central macrophage surrounded by developing erythroblasts, were described. However, the in vivo role of macrophages in erythropoiesis under homeostatic conditions or in disease remains unclear. We found that specific depletion of CD169 + macrophages markedly reduced the number of erythroblasts in the bone marrow but did not result in overt anemia under homeostatic conditions, probably because of concomitant alterations in red blood cell clearance. However, CD169 + macrophage depletion significantly impaired erythropoietic recovery from hemolytic anemia, acute blood loss and myeloablation. Furthermore, macrophage depletion normalized the erythroid compartment in a JAK2 V617F -driven mouse model of polycythemia vera, suggesting that erythropoiesis in polycythemia vera remains under the control of macrophages in the bone marrow and splenic microenvironments. These results indicate that CD169 + macrophages promote late erythroid maturation and that modulation of the macrophage compartment may be a new strategy to treat erythropoietic disorders.

Prophylactic use of letermovir (LMV) markedly reduces the incidence of early clinically significant cytomegalovirus (csCMV) infection within the first 100 days after allogeneic hematopoietic cell transplantation (allo-HCT), which improves transplant outcomes. However, some patients eventually develop late-csCMV infection (beyond day 100) after completing LMV prophylaxis. To assess the incidence of late-csCMV infection as well as its risk factors and impacts on transplant outcome, a total of 81 allo-HCT recipients who had not developed early csCMV infection during LMV prophylaxis were retrospectively analyzed. Among them, 23 (28.4%) patients developed late-csCMV infection (until day 180) at a median time of 131 days after transplantation and 30 days after LMV discontinuation, respectively. Late-csCMV infection was correlated with apparent delayed immune reconstitution: patients transplanted from HLA-mismatched donors (hazard ratio [HR] = 13.0, p = 0.011) or CMV-IgG-negative donors (HR = 2.39, p = 0.043) had a significantly higher risk. In this study, transplant outcomes did not differ between patients with and without late-csCMV infection. This suggests a need to clarify the efficacy of extended administration of LMV for preventing late-csCMV infection in a larger number of allo-HCT recipients, especially those with “high-risk” donors.

The balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) maintains hematopoietic homeostasis, failure of which can lead to hematopoietic disorder. HSPC fate is controlled by signals from the bone marrow niche resulting in alteration of the stem cell transcription network. Regnase-1, a member of the CCCH zinc finger protein family possessing RNAse activity, mediates post-transcriptional regulatory activity through degradation of target mRNAs. The precise function of Regnase-1 has been explored in inflammation-related cytokine expression but its function in hematopoiesis has not been elucidated. Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA. In addition, we found that dysfunction of Regnase-1 leads to the rapid onset of abnormal hematopoiesis. Thus, our data reveal that Regnase-1-mediated post-transcriptional regulation is required for HSPC maintenance and suggest that it represents a leukemia tumor suppressor. Regnase-1 is known to mediate post-trasncriptional regulatory activity through degradation of target mRNAs. Here, the authors show that Regnase-1 regulates self-renewal of haematopoietic stem and progenitor cells through modulation of the stability of Gata2 and Tal1 mRNA.

Congenital antithrombin (AT) or serpin C1 deficiency, caused by a SERPINC1 abnormality, is a high-risk factor for venous thrombosis. SERPINC1 is prone to genetic rearrangement, because it contains numerous Alu elements. In this study, a Japanese patient who developed deep vein thrombosis during pregnancy and exhibited low AT activity underwent SERPINC1 gene analysis using routine methods: long-range polymerase chain reaction (PCR) and real-time PCR. Sequencing using long-range PCR products revealed no pathological variants in SERPINC1 exons or exon–intron junctions, and all the identified variants were homozygous, suggesting a deletion in one SERPINC1 allele. Copy number quantification for each SERPINC1 exon using real-time PCR revealed half the number of exon 1 and 2 copies compared with controls. Moreover, a deletion region was deduced by quantifying the 5′-upstream region copy number of SERPINC1 for each constant region. Direct long-range PCR sequencing with primers for the 5'-end of each presumed deletion region revealed a large Alu -mediated deletion (∼13 kb) involving SERPINC1 exons 1 and 2. Thus, a large deletion was identified in SERPINC1 using conventional PCR methods.

The fate decision of hematopoietic stem cells (HSCs), quiescence, proliferation or differentiation, is uniquely determined by functionally specialized microenvironments defined as the HSC niches. However, whether quiescence and proliferation of HSCs are regulated by spatially distinct niches is unclear. Although various candidate stromal cells have been identified as potential niche cells, the spatial localization of quiescent HSCs in the bone marrow remains controversial. In our recent study, we have established whole-mount confocal immunofluorescence techniques, which allow us to precisely assess the localization of HSCs and their relationships with stromal structures. Furthermore, we have assessed the significance of these associations using a computational simulation. These novel analyses have revealed that quiescent HSCs are specifically associated with small caliber arterioles, which are predominantly distributed in the endosteal bone marrow while the associations with sinusoidal vessels or osteoblasts are not significant. Physical ablation of the arteriolar niche causes the shift of HSC localization to sinusoidal niches, where HSCs are switched into non-quiescent status. This new imaging analyses together with previous studies suggest the presence of spatially distinct vascular niches for quiescent and non-quiescent (proliferating) HSCs in the bone marrow.