Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults. While complete remission can be obtained with intensive chemotherapy in young and fit patients, relapse is frequent ...and prognosis remains poor. Leukemic cells are thought to arise from a pool of leukemic stem cells (LSCs) which sit at the top of the hierarchy. Since their discovery, more than 30 years ago, LSCs have been a topic of intense research and their identification paved the way for cancer stem cell research. LSCs are defined by their ability to self-renew, to engraft into recipient mice and to give rise to leukemia. Compared to healthy hematopoietic stem cells (HSCs), LSCs display specific mutations, epigenetic modifications, and a specific metabolic profile. LSCs are usually considered resistant to chemotherapy and are therefore the drivers of relapse. Similar to their HSC counterpart, LSCs reside in a highly specialized microenvironment referred to as the "niche". Bidirectional interactions between leukemic cells and the microenvironment favor leukemic progression at the expense of healthy hematopoiesis. Within the niche, LSCs are thought to be protected from genotoxic insults. Improvement in our understanding of LSC gene expression profile and phenotype has led to the development of prognosis signatures and the identification of potential therapeutic targets. In this review, we will discuss LSC biology in the context of their specific microenvironment and how a better understanding of LSC niche biology could pave the way for new therapies that target AML.
Mesenchymal stem cells (MSCs) are self-renewing precursor cells that can differentiate into bone, fat, cartilage, and stromal cells of the bone marrow. Recent studies suggest that MSCs themselves are ...critical for forming a niche that maintains hematopoietic stem cells (HSCs). The ease by which human MSC-like and stromal progenitor cells can be isolated from the bone marrow and other tissues has led to the rapid development of clinical investigations exploring their anti-inflammatory properties, tissue preservation capabilities, and regenerative potential. However, the identity of genuine MSCs and their specific contributions to these various beneficial effects have remained enigmatic. In this article, we examine the definition of MSCs and discuss the importance of rigorously characterizing their stem cell activity. We review their role and that of other putative niche constituents in the regulation of bone marrow HSCs. Additionally, how MSCs and their stromal progeny alter immune function is discussed, as well as potential therapeutic implications.
The spatial localization of hematopoietic stem cells (HSCs) in the bone marrow (BM) remains controversial, with some studies suggesting that they are maintained in homogeneously distributed niches ...while others have suggested the contributions of distinct niche structures. Subsets of quiescent HSCs have been reported to associate with megakaryocytes (MK) or arterioles in the BM. However, these HSC subsets have not been prospectively defined. Here, we show that platelet and myeloid-biased HSCs, marked by von Willebrand factor (vWF) expression, are highly enriched in MK niches. Depletion of MK selectively expands vWF+ HSCs, whereas the depletion of NG2+ arteriolar niche cells selectively depletes vWF− lymphoid-biased HSCs. In addition, MK depletion compromises vWF+ HSC function by reducing their long-term self-renewal capacity and eliminating their lineage bias after transplantation. These studies demonstrate the existence of two spatially and functionally separate BM niches for HSC subsets with distinct developmental potential.
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•Platelet- and myeloid-biased vWF+ HSCs associate with MK, but not arteriolar niches•vWF+, but not lymphoid-biased vWF− HSC proliferation, is regulated by MK•vWF+ HSC reconstitution potential is regulated by MK•NG2+ arteriolar niches selectively regulate vWF− HSC quiescence and localization
Pinho et al. show that myeloid- and lymphoid-biased HSCs are located in, and regulated by, separate bone marrow niches occupied by megakaryocytes (MK) and arterioles, respectively. MK niches may also regulate HSC fate since MK deletion reprograms myeloid-biased HSCs to balanced-lineage contributions.
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.
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.
Mesenchymal stem and progenitor cells (MSPCs) contribute to bone marrow (BM) homeostasis by generating multiple types of stromal cells. MSPCs can be labeled in the adult BM by Nestin-GFP, whereas ...committed osteoblast progenitors are marked by Osterix expression. However, the developmental origin and hierarchical relationship of stromal cells remain largely unknown. Here, by using a lineage-tracing system, we describe three distinct waves of contributions of Osterix+ cells in the BM. First, Osterix+ progenitors in the fetal BM contribute to nascent bone tissues and transient stromal cells that are replaced in the adult marrow. Second, Osterix-expressing cells perinatally contribute to osteolineages and long-lived BM stroma, which have characteristics of Nestin-GFP+ MSPCs. Third, Osterix labeling in the adult marrow is osteolineage-restricted, devoid of stromal contribution. These results uncover a broad expression profile of Osterix and raise the intriguing possibility that distinct waves of stromal cells, primitive and definitive, may organize the developing BM.
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•Fetal Osterix+ cells give rise to a primitive stroma that is replaced after birth•Neonatal Osterix+ cells contribute to long-lived, definitive stroma•Neonatal Osterix-derived BM stromal cells mark definitive MSPCs in the adult•Osterix-derived MSPCs contribute to tissue regeneration after injury
Bone marrow (BM) mesenchymal stem and progenitor cells (MSPCs) generate multiple types of stromal cells. However, the origin of MSPCs remains unknown. Mizoguchi et al. show that Osterix-expressing cells mark at least three waves of progenitors during BM development and that definitive Nestin+ long-lived stromal progenitors are established during the perinatal stage.
Perivascular mesenchymal stem and progenitor cells (MSPCs) are critical for forming a healthy hematopoietic stem cell (HSC) niche. However, the interactions and influence of acute myelogenous ...leukemia (AML) stem cells with the microenvironment remain largely unexplored. We have unexpectedly found that neuropathy of the sympathetic nervous system (SNS) promotes leukemic bone marrow infiltration in an MLL-AF9 AML model. Development of AML disrupts SNS nerves and the quiescence of Nestin+ niche cells, leading to an expansion of phenotypic MSPCs primed for osteoblastic differentiation at the expense of HSC-maintaining NG2+ periarteriolar niche cells. Adrenergic signaling promoting leukemogenesis is transduced by the β2, but not β3, adrenergic receptor expressed on stromal cells of leukemic bone marrow. These results indicate that sympathetic neuropathy may represent a mechanism for the malignancy in order to co-opt the microenvironment and suggest separate mesenchymal niche activities for malignant and healthy hematopoietic stem cells in the bone marrow.
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•AML leads to sympathetic neuropathy and expansion of an altered bone marrow niche•MSC differentiation is enhanced toward osteoprogenitors with maturation arrest•AML reduces NG2+ cell numbers and HSC niche regulating activity•Sympathetic neuropathy promotes AML through stromal Adrβ2
Development of acute myelogenous leukemia (AML) disrupts sympathetic nerves and the quiescence of Nestin+ niche cells, enhancing expansion of phenotypic mesenchymal stem/progenitor cells primed for osteoblastic differentiation at the expense of HSC-maintaining NG2+ periarteriolar niche cells.
Host microbiota crosstalk is essential for the production and functional modulation of blood-cell lineages. Whether, and if so how, the microbiota influences hematopoietic stem cells (HSCs) is ...unclear. Here, we show that the microbiota regulates HSC self-renewal and differentiation under stress conditions by modulating local iron availability in the bone marrow (BM). In microbiota-depleted mice, HSC self-renewal was enhanced during regeneration, while the commitment toward differentiation was dramatically compromised. Mechanistically, microbiota depletion selectively impaired the recycling of red blood cells (RBCs) by BM macrophages, resulting in reduced local iron levels without affecting systemic iron homeostasis. Limiting iron availability in food (in vivo) or in culture (ex vivo), or by CD169+ macrophage depletion, enhanced HSC self-renewal and expansion. These results reveal an intricate interplay between the microbiota, macrophages, and iron, and their essential roles in regulating critical HSC fate decisions under stress.
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•Microbiota depletion impairs HSC response under stress conditions•BM macrophages recycle RBCs to provide iron to HSCs for regeneration•The microbiota regulates BM macrophage functions via short-chain fatty acid•Local iron availability controls HSC self-renewal and differentiation decisions
Zhang et al. show that the gut microbiota regulates RBC recycling by BM macrophages under stress conditions, which ensures rapid iron access in the BM to control HSC self-renewal and differentiation. Thus, a microbiota-macrophage-iron axis plays an essential role in regulating HSC fate decisions.
The classic definition of precocious sexual maturation is the development of secondary sexual characteristics before 8 years of age in girls and before 9 years of age in boys. It is classified as ...central precocious puberty when premature maturation of the hypothalamic-pituitary-gonadal axis occurs, and as peripheral precocious puberty when there is excessive secretion of sex hormones, independent of gonadotropin secretion. Precocious sexual maturation is more common in girls, generally central precocious puberty of idiopathic origin. In boys, it tends to be linked to central nervous system abnormalities. Clinical evaluation should include a detailed history and physical examination, including anthropometric measurements, calculation of growth velocity, and evaluation of secondary sexual characteristics. The main sign to suspect the onset of puberty is breast tissue development (thelarche) in girls and testicular enlargement (≥4 mL) in boys. Hormonal assessment and imaging are required for diagnosis and identification of the etiology. Genetic testing should be considered if there is a family history of precocious puberty or other clinical features suggestive of a genetic syndrome. Long-acting gonadotropin-releasing hormone analogs are the standard of care for central precocious puberty management, while peripheral precocious puberty management depends on the etiology.
Conclusion
: The aim of this review is to address the epidemiology, etiology, clinical assessment, and management of precocious sexual maturation.
What is Known:
• The main sign to suspect the onset of puberty is breast tissue development (thelarche) in girls and testicular enlargement (≥4 mL) in boys. The classic definition of precocious sexual maturation is the development of secondary sexual characteristics before 8 years of age in girls and before 9 years of age in boys.
• Long-acting gonadotropin-releasing hormone agonist (GnRHa) is the standard of care for CPP management, and adequate hormone suppression results in the stabilization of pubertal progression, a decline in growth velocity, and a decrease in bone age advancement.
What is New:
• Most cases of precocious sexual maturation are gonadotropin-dependent and currently assumed to be idiopathic, but mutations in genes involved in pubertal development have been identified, such as MKRN3 and DLK1.
• A different preparation of long-acting GnRHa is now available: 6-month subcutaneous injection.
The aim of this study was to establish a peptidomic profile based on LC-MS/MS and random forest (RF) algorithm to distinguish the urinary peptidomic scenario of type 2 diabetes mellitus (T2DM) ...patients with different stages of diabetic kidney disease (DKD). Urine from 60 T2DM patients was collected: 22 normal (stage A1), 18 moderately increased (stage A2) and 20 severely increased (stage A3) albuminuria. A total of 1080 naturally occurring peptides were detected, which resulted in the identification of a total of 100 proteins, irrespective of the patients' renal status. The classification accuracy showed that the most severe DKD (A3) presented a distinct urinary peptidomic pattern. Estimates for peptide importance assessed during RF model training included multiple fragments of collagen and alpha-1 antitrypsin, previously associated to DKD. Proteasix tool predicted 48 proteases potentially involved in the generation of the 60 most important peptides identified in the urine of DM patients, including metallopeptidases, cathepsins, and calpains. Collectively, our study lightened some biomarkers possibly involved in the pathogenic mechanisms of DKD, suggesting that peptidomics is a valuable tool for identifying the molecular mechanisms underpinning the disease and thus novel therapeutic targets.
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