Molecular interactome between HSCs and their niches.

Because hematopoietic stem cells (HSCs) were found to require a bone marrow (BM) habitat for long-term function, many studies have attempted to dissect key cellular and molecular interactions between HSCs and their BM microenvironments or HSC niches. In this issue of Blood, Mende et al provide a computational method to infer potential ligand-receptor interactions between murine hematopoietic stem and progenitor cells (HSPCs) and their niche-forming cells

Human and mouse leukocytes: different clockwork.

In this issue of Blood, Zhao et al use a humanized mouse model to investigate the mechanisms driving daily oscillations in circulating human and murine leukocytes.1 In the same mice, they find human and murine circulating leukocytes displaying inverted oscillations, reproducing the trafficking pattern previously observed in both species. A novel network regulating circadian leukocyte trafficking is proposed. It involves interspecies differences of stress-kinase regulation of reactive oxygen species (ROS), hypoxia-inducible factor 1a (HIF-1a) and clock gene–dependent regulation of the CXCL12 receptor CXCR4. This study underscores the crosstalk of the genetic clock with metabolism and ROS in the regulation of leukocyte migration and reveals new mechanistic players

Neuronal regulation of bone marrow stem cell niches.

The bone marrow (BM) is the primary site of postnatal hematopoiesis and hematopoietic stem cell (HSC) maintenance. The BM HSC niche is an essential microenvironment which evolves and responds to the physiological demands of HSCs. It is responsible for orchestrating the fate of HSCs and tightly regulates the processes that occur in the BM, including self-renewal, quiescence, engraftment, and lineage differentiation. However, the BM HSC niche is disturbed following hematological stress such as hematological malignancies, ionizing radiation, and chemotherapy, causing the cellular composition to alter and remodeling to occur. Consequently, hematopoietic recovery has been the focus of many recent studies and elucidating these mechanisms has great biological and clinical relevance, namely to exploit these mechanisms as a therapeutic treatment for hematopoietic malignancies and improve regeneration following BM injury. The sympathetic nervous system innervates the BM niche and regulates the migration of HSCs in and out of the BM under steady state. However, recent studies have investigated how sympathetic innervation and signaling are dysregulated under stress and the subsequent effect they have on hematopoiesis. Here, we provide an overview of distinct BM niches and how they contribute to HSC regulatory processes with a particular focus on neuronal regulation of HSCs under steady state and stress hematopoiesis

The hematopoietic stem-cell niche in health and leukemia.

Research in the last decade has shown that hematopoietic stem cells (HSCs) interact with and are modulated by a complex multicellular microenvironment in the bone marrow, which includes both the HSC progeny and multiple non-hematopoietic cell types. Intense work is gradually throwing light on the composition of the HSC niche and the molecular cues exchanged between its components, which has implications for HSC production, maintenance and expansion. In addition, it has become apparent that bidirectional interactions between leukemic cells and their niche play a previously unrecognized role in the initiation and development of hematological malignancies. Consequently, targeting of the malignant niche holds considerable promise for more specific antileukemic therapies. Here we summarize the latest insights into HSC niche biology and recent work showing multiple connections between hematological malignancy and alterations in the bone marrow microenvironment.This work was supported by core support grants from the Wellcome Trust and MRC to the Cambridge Stem Cell Institute, the Spanish Ministry of Economy and Competitiveness (SAF-2011-30308), Pro-CNIC Foundation, Severo Ochoa Center of Excellence award SEV-2015-0505 to CNIC, TerCel (Spanish Cell Therapy Network), Ramón y Cajal Program grants RYC-2011-09726 to AS-A and RYC-2009-04703 to SM-F), Marie Curie Career Integration Program grants (FP7-PEOPLE-2011-RG-294262/294096) to AS-A and SM-F; and a ConSEPOC-Comunidad de Madrid grant (S2010/BMD-2542) and Horizon2020 (ERC-2014-CoG-64765 grant to SM-F. This research was partly funded by a European Hematology Association Research Fellowship awarded to AS-A and an International Early Career Scientist Grant from the Howard Hughes Medical Institute to SM-F.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00018-016-2306-

Microenvironmental contributions to hematopoietic stem cell aging.

Hematopoietic stem cell (HSC) aging was originally thought to be essentially an HSC-autonomous process, which is the focus of another review in the same issue of Haematologica However, studies on the microenvironment that maintains and regulates HSC (HSC niche) over the past 20 years have suggested that microenvironmental aging contributes to declined HSC function over time. The HSC niches comprise a complex and dynamic molecular network of interactions across multiple cell types, including endothelial cells, mesenchymal stromal cells, osteoblasts, adipocytes, neuroglial cells and mature hematopoietic cells. Upon aging, functional changes in the HSC niches, such as microenvironmental senescence, imbalanced bone marrow mesenchymal stromal cell differentiation, vascular remodeling, changes in adrenergic signaling and inflammation, coordinately and dynamically influence the fate of HSC and their downstream progeny. The end result is lymphoid deficiency and myeloid skewing. During this process, aged HSC and their derivatives remodel the niche to favor myeloid expansion. Therefore, the crosstalk between HSC and the microenvironment is indispensable for the aging of the hematopoietic system and might represent a therapeutic target in age-related pathological disorders

Stem cells "aclymatise" to regenerate the blood system.

How blood stem cells balance fate decisions between quiescence maintenance and differentiation during recovery from cancer treatment remains poorly understood. A recent study by Umemoto et al (2022) uncovers an unexpected linkage between metabolic and epigenetic regulation of haematopoiesis, suggesting new targets in haematopoietic regeneration, with possible implications in leukaemogenesis and therapy resistance

Cellular Heterogeneity of Mesenchymal Stem/Stromal Cells in the Bone Marrow.

Mesenchymal stem/stromal cells (MSCs) are present in various body tissues and help in maintaining homeostasis. The stemness of MSCs has been evaluated in vitro. In addition, analyses of cell surface antigens and gene expression patterns have shown that MSCs comprise a heterogeneous population, and the diverse and complex nature of MSCs makes it difficult to identify the specific roles in diseases. There is a lack of understanding regarding the classification of MSC properties. In this review, we explore the characteristics of heterogeneous MSC populations based on their markers and gene expression profiles. We integrated the contents of previously reported single-cell analysis data to better understand the properties of mesenchymal cell populations. In addition, the cell populations involved in the development of myeloproliferative neoplasms (MPNs) are outlined. Owing to the diversity of terms used to describe MSCs, we used the text mining technology to extract topics from MSC research articles. Recent advances in technology could improve our understanding of the diversity of MSCs and help us evaluate cell populations

Megakaryocyte Diversity in Ontogeny, Functions and Cell-Cell Interactions

Hematopoietic stem cells (HSCs) rely on local interactions in the bone marrow (BM) microenvironment with stromal cells and other hematopoietic cells that facilitate their survival and proliferation, and also regulate their functions. HSCs and multipotent progenitor cells differentiate into lineage-specific progenitors that generate all blood and immune cells. Megakaryocytes (Mks) are hematopoietic cells responsible for producing blood platelets, which are essential for normal hemostasis and blood coagulation. Although the most prominent function of Mks is platelet production (thrombopoiesis), other increasingly recognized functions include HSC maintenance and host immune response. However, whether and how these diverse programs are executed by different Mk subpopulations remains poorly understood. This Perspective summarizes our current understanding of diversity in ontogeny, functions and cell-cell interactions. Cumulative evidence suggests that BM microenvironment dysfunction, partly caused by mutated Mks, can induce or alter the progression of a variety of hematologic malignancies, including myeloproliferative neoplasms (MPNs) and other disorders associated with tissue scarring (fibrosis). Therefore, as an example of the heterogeneous functions of Mks in malignant hematopoiesis, we will discuss the role of Mks in the onset and progression of BM fibrosis. In this regard, abnormal interactions between of Mks and other immune cells might directly contribute to fibrotic diseases. Overall, further understanding of megakaryopoiesis and how Mks interact with HSCs and immune cells has potential clinical implications for stem cell transplantation and other therapies for hematologic malignancies, as well as for treatments to stimulate platelet production and prevent thrombocytopenia

Trophic restoration of the nigrostriatal dopaminergic pathway in long-term carotid body-grafted parkinsonian rats

We studied the mechanisms underlying long-term functional recovery of hemiparkinsonian rats grafted intrastriatally with carotid body (CB) cell aggregates. Amelioration of their motor syndrome is a result of the trophic actions of these grafts on the remaining ipsilateral substantia nigra neurons rather than of the release of dopamine from the CB grafts. The grafts maintain a stable morphological appearance and differentiated cell phenotype for the duration of the life of the host. Adult CB expresses high levels of glial cell line-derived neurotrophic factor (GDNF) and the multicomponent GDNF receptor complex. These properties may contribute to the trophic actions of the CB transplants on nigrostriatal neurons and to their extraordinary longevity. We show that CB glomus cells, although highly dopaminergic, are protected from dopamine-mediated oxidative damage because of the absence of the high-affinity dopamine transporter. Thus, intrastriatal CB grafts are uniquely suited for long-term delivery of trophic factors capable of promoting restoration of the nigrostriatal pathway