scholarly journals CXCL12-abundant Reticular Cells are the Major Source of IL-6 Upon LPS-stimulation and Thereby Regulate Hematopoiesis

2021 ◽  
Author(s):  
Rahel Gerosa ◽  
Steffen Boettcher ◽  
Larisa Vladimirovna Kovtonyuk ◽  
Annika Hausmann ◽  
Wolf-Dietrich Hardt ◽  
...  
Keyword(s):  
Initial Phase ◽  
Essential Role ◽  
Cell Types ◽  
Cell Populations ◽  
Cell Contact ◽  
Hematopoietic Stem ◽  
Gene Expression Analyses ◽  
Stem And Progenitor Cells ◽  
Reticular Cells

Hematopoiesis is maintained by hematopoietic stem and progenitor cells (HSPCs) that are located in the bone marrow (BM) where they are embedded within a complex supportive microenvironment, consisting of a multitude of various non-hematopoietic and hematopoietic cell types. The BM microenvironment not only regulates steady-state hematopoiesis by provision of growth factors, cytokines and cell-cell contact but is also an emerging key player during the adaptation to infectious and inflammatory insults (emergency hematopoiesis). Through a combination of gene expression analyses in prospectively isolated non-hematopoietic BM cell populations and various mouse models we have revealed that BM CXCL12-abundant reticular (CAR) cells are a major source of systemic and local BM IL-6 levels during emergency hematopoiesis following lipopolysaccharide (LPS) stimulation. Importantly, while IL-6 is dispensable during the initial phase of LPS-induced emergency hematopoiesis, it is required to sustain an adequate hematopoietic output during chronic-repetitive inflammation. Our data highlight the essential role of the non-hematopoietic BM microenvironment for the sensing and integration of pathogen-derived signals into sustained demand-adapted hematopoietic responses.

scholarly journals The hemogenic endothelium: a critical source for the generation of PSC-derived hematopoietic stem and progenitor cells

2021 ◽  
Author(s):  
Lucas Lange ◽  
Michael Morgan ◽  
Axel Schambach
Keyword(s):  
Stem Cells ◽  
De Novo ◽  
Cell Types ◽  
Hemogenic Endothelium ◽  
Hematopoietic Stem ◽  
Autologous Cell ◽  
Stem And Progenitor Cells ◽  
Bona Fide

AbstractIn vitro generation of hematopoietic cells and especially hematopoietic stem cells (HSCs) from human pluripotent stem cells (PSCs) are subject to intensive research in recent decades, as these cells hold great potential for regenerative medicine and autologous cell replacement therapies. Despite many attempts, in vitro, de novo generation of bona fide HSCs remains challenging, and we are still far away from their clinical use, due to insufficient functionality and quantity of the produced HSCs. The challenges of generating PSC-derived HSCs are already apparent in early stages of hemato-endothelial specification with the limitation of recapitulating complex, dynamic processes of embryonic hematopoietic ontogeny in vitro. Further, these current shortcomings imply the incompleteness of our understanding of human ontogenetic processes from embryonic mesoderm over an intermediate, specialized hemogenic endothelium (HE) to their immediate progeny, the HSCs. In this review, we examine the recent investigations of hemato-endothelial ontogeny and recently reported progress for the conversion of PSCs and other promising somatic cell types towards HSCs with the focus on the crucial and inevitable role of the HE to achieve the long-standing goal—to generate therapeutically applicable PSC-derived HSCs in vitro.

scholarly journals The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Brianna J. Klein ◽  
Anagha Deshpande ◽  
Khan L. Cox ◽  
Fan Xuan ◽  
Mohamad Zandian ◽  
...  
Keyword(s):  
Critical Role ◽  
Cellular Transformation ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Nucleosome Core ◽  
Stem And Progenitor Cells ◽  
Transforming Activity

AbstractChromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10PZP-dependent CALM-AF10-mediated leukemogenesis.

scholarly journals Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes

Blood ◽  
2019 ◽  
Vol 133 (3) ◽  
pp. 224-236 ◽  
Author(s):  
Andrés García-García ◽  
Claudia Korn ◽  
María García-Fernández ◽  
Olivia Domingues ◽  
Javier Villadiego ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Nervous System ◽  
Adrenergic Receptor ◽  
Leukocyte Trafficking ◽  
Vascular Cell Adhesion ◽  
Cholinergic Activity ◽  
Vascular Cell ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

AbstractHematopoietic stem and progenitor cells (HSPCs) and leukocytes circulate between the bone marrow (BM) and peripheral blood following circadian oscillations. Autonomic sympathetic noradrenergic signals have been shown to regulate HSPC and leukocyte trafficking, but the role of the cholinergic branch has remained unexplored. We have investigated the role of the cholinergic nervous system in the regulation of day/night traffic of HSPCs and leukocytes in mice. We show here that the autonomic cholinergic nervous system (including parasympathetic and sympathetic) dually regulates daily migration of HSPCs and leukocytes. At night, central parasympathetic cholinergic signals dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes. However, during the daytime, derepressed sympathetic noradrenergic activity causes predominant BM egress of HSPCs and leukocytes via β3–adrenergic receptor. This egress is locally supported by light-triggered sympathetic cholinergic activity, which inhibits BM vascular cell adhesion and homing. In summary, central (parasympathetic) and local (sympathetic) cholinergic signals regulate day/night oscillations of circulating HSPCs and leukocytes. This study shows how both branches of the autonomic nervous system cooperate to orchestrate daily traffic of HSPCs and leukocytes.

scholarly journals Bone marrow regeneration requires mitochondrial transfer from donor Cx43-expressing hematopoietic progenitors to stroma

Blood ◽  
2020 ◽  
Vol 136 (23) ◽  
pp. 2607-2619 ◽  
Author(s):  
Karin Golan ◽  
Abhishek K. Singh ◽  
Orit Kollet ◽  
Mayla Bertagna ◽  
Mark J. Althoff ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Connexin 43 ◽  
Purinergic Receptor ◽  
Cell Contact ◽  
Hematopoietic Stem ◽  
Mitochondrial Transfer ◽  
Stem And Progenitor Cells ◽  
Mitochondria Transfer ◽  
Bone Marrow Regeneration

Abstract The fate of hematopoietic stem and progenitor cells (HSPC) is tightly regulated by their bone marrow (BM) microenvironment (ME). BM transplantation (BMT) frequently requires irradiation preconditioning to ablate endogenous hematopoietic cells. Whether the stromal ME is damaged and how it recovers after irradiation is unknown. We report that BM mesenchymal stromal cells (MSC) undergo massive damage to their mitochondrial function after irradiation. Donor healthy HSPC transfer functional mitochondria to the stromal ME, thus improving mitochondria activity in recipient MSC. Mitochondrial transfer to MSC is cell-contact dependent and mediated by HSPC connexin-43 (Cx43). Hematopoietic Cx43-deficient chimeric mice show reduced mitochondria transfer, which was rescued upon re-expression of Cx43 in HSPC or culture with isolated mitochondria from Cx43 deficient HSPCs. Increased intracellular adenosine triphosphate levels activate the purinergic receptor P2RX7 and lead to reduced activity of adenosine 5′-monophosphate–activated protein kinase (AMPK) in HSPC, dramatically increasing mitochondria transfer to BM MSC. Host stromal ME recovery and donor HSPC engraftment were augmented after mitochondria transfer. Deficiency of Cx43 delayed mesenchymal and osteogenic regeneration while in vivo AMPK inhibition increased stromal recovery. As a consequence, the hematopoietic compartment reconstitution was improved because of the recovery of the supportive stromal ME. Our findings demonstrate that healthy donor HSPC not only reconstitute the hematopoietic system after transplantation, but also support and induce the metabolic recovery of their irradiated, damaged ME via mitochondria transfer. Understanding the mechanisms regulating stromal recovery after myeloablative stress are of high clinical interest to optimize BMT procedures and underscore the importance of accessory, non-HSC to accelerate hematopoietic engraftment.

scholarly journals Adult blood stem cell localization reflects the abundance of reported bone marrow niche cell types and their combinations

Blood ◽  
2020 ◽  
Vol 136 (20) ◽  
pp. 2296-2307 ◽  
Author(s):  
Konstantinos D. Kokkaliaris ◽  
Leo Kunz ◽  
Nina Cabezas-Wallscheid ◽  
Constantina Christodoulou ◽  
Simon Renders ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Types ◽  
Bone Marrow Niche ◽  
Functional Heterogeneity ◽  
Hematopoietic Stem ◽  
Native Bone ◽  
Cell Localization ◽  
Exact Localization ◽  
Stem And Progenitor Cells ◽  
Multiple Cell

Abstract The exact localization of hematopoietic stem cells (HSCs) in their native bone marrow (BM) microenvironment remains controversial, because multiple cell types have been reported to physically associate with HSCs. In this study, we comprehensively quantified HSC localization with up to 4 simultaneous (9 total) BM components in 152 full-bone sections from different bone types and 3 HSC reporter lines. We found adult femoral α-catulin-GFP+ or Mds1GFP/+Flt3Cre HSCs proximal to sinusoids, Cxcl12 stroma, megakaryocytes, and different combinations of those populations, but not proximal to bone, adipocyte, periarteriolar, or Schwann cells. Despite microanatomical differences in femurs and sterna, their adult α-catulin-GFP+ HSCs had similar distributions. Importantly, their microenvironmental localizations were not different from those of random dots, reflecting the relative abundance of imaged BM populations rather than active enrichment. Despite their functional heterogeneity, dormant label-retaining (LR) and non-LR hematopoietic stem and progenitor cells both had indistinguishable localization from α-catulin-GFP+ HSCs. In contrast, cycling juvenile BM HSCs preferentially located close to Cxcl12 stroma and farther from sinusoids/megakaryocytes. We expect our study to help resolve existing confusion regarding the exact localization of different HSC types, their physical association with described BM populations, and their tissue-wide combinations.

scholarly journals Extreme disruption of heterochromatin is required for accelerated hematopoietic aging

Blood ◽  
2020 ◽  
Vol 135 (23) ◽  
pp. 2049-2058 ◽  
Author(s):  
Christine R. Keenan ◽  
Nadia Iannarella ◽  
Gaetano Naselli ◽  
Naiara G. Bediaga ◽  
Timothy M. Johanson ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Function ◽  
Cell Types ◽  
Premature Aging ◽  
Thymic Involution ◽  
Hematopoietic Stem ◽  
Hematopoietic System

Abstract Loss of heterochromatin has been proposed as a universal mechanism of aging across different species and cell types. However, a comprehensive analysis of hematopoietic changes caused by heterochromatin loss is lacking. Moreover, there is conflict in the literature around the role of the major heterochromatic histone methyltransferase Suv39h1 in the aging process. Here, we use individual and dual deletion of Suv39h1 and Suv39h2 enzymes to examine the causal role of heterochromatin loss in hematopoietic cell development. Loss of neither Suv39h1 nor Suv39h2 individually had any effect on hematopoietic stem cell function or the development of mature lymphoid or myeloid lineages. However, deletion of both enzymes resulted in characteristic changes associated with aging such as reduced hematopoietic stem cell function, thymic involution and decreased lymphoid output with a skewing toward myeloid development, and increased memory T cells at the expense of naive T cells. These cellular changes were accompanied by molecular changes consistent with aging, including alterations in nuclear shape and increased nucleolar size. Together, our results indicate that the hematopoietic system has a remarkable tolerance for major disruptions in chromatin structure and reveal a role for Suv39h2 in depositing sufficient H3K9me3 to protect the entire hematopoietic system from changes associated with premature aging.

scholarly journals Rapid and sustained hematopoietic recovery in lethally irradiated mice transplanted with purified Thy-1.1lo Lin-Sca-1+ hematopoietic stem cells

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3758-3779 ◽  
Author(s):  
N Uchida ◽  
HL Aguila ◽  
WH Fleming ◽  
L Jerabek ◽  
IL Weissman
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Blood Cells ◽  
Critical Role ◽  
White Blood Cells ◽  
Cell Types ◽  
Dose Dependence ◽  
Hematopoietic Stem ◽  
Hematopoietic Recovery

Abstract Hematopoietic stem cells (HSCs) are believed to play a critical role in the sustained repopulation of all blood cells after bone marrow transplantation (BMT). However, understanding the role of HSCs versus other hematopoietic cells in the quantitative reconstitution of various blood cell types has awaited methods to isolate HSCs. A candidate population of mouse HSCs, Thy-1.1lo Lin-Sca-1+ cells, was isolated several years ago and, recently, this population has been shown to be the only population of BM cells that contains HSCs in C57BL/Ka-Thy-1.1 mice. As few as 100 of these cells can radioprotect 95% to 100% of irradiated mice, resulting long-term multilineage reconstitution. In this study, we examined the reconstitution potential of irradiated mice transplanted with purified Thy-1.1lo Lin-Sca-1+ BM cells. Donor-derived peripheral blood (PB) white blood cells were detected as early as day 9 or 10 when 100 to 1,000 Thy-1.1lo Lin-Sca-1+ cells were used, with minor dose-dependent differences. The reappearance of platelets by day 14 and thereafter was also seen at all HSC doses (100 to 1,000 cells), with a slight dose-dependence. All studied HSC doses also allowed RBC levels to recover, although at the 100 cell dose a delay in hematocrit recovery was observed at day 14. When irradiated mice were transplanted with 500 Thy-1.1lo Lin-Sca-1+ cells compared with 1 x 10(6) BM cells (the equivalent amount of cells that contain 500 Thy-1.1lo Lin-Sca-1+ cells as well as progenitor and mature cells), very little difference in the kinetics of recovery of PB, white blood cells, platelets, and hematocrit was observed. Surprisingly, even when 200 Thy1.1lo Lin-Sca- 1+ cells were mixed with 4 x 10(5) Sca-1- BM cells in a competitive repopulation assay, most of the early (days 11 and 14) PB myeloid cells were derived from the HSC genotype, indicating the superiority of the Thy-1.1lo Lin-Sca-1+ cells over Sca-1- cells even in the early phases of myeloid reconstitution. Within the Thy-1.1lo Lin-Sca-1+ population, the Rhodamine 123 (Rh123)hi subset dominates in PB myeloid reconstitution at 10 to 14 days, only to be overtaken by the Rh123lo subset at 3 weeks and thereafter. These findings indicate that HSCs can account for the early phase of hematopoietic recovery, as well as sustained hematopoiesis, and raise questions about the role of non-HSC BM populations in the setting of BMT.

scholarly journals Aldehyde Dehydrogenases: Not Just Markers, but Functional Regulators of Stem Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Giuseppe Vassalli
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cellular Function ◽  
Stem Cell Marker ◽  
Cell Populations ◽  
Aldh Activity ◽  
Cellular Functions ◽  
Stem And Progenitor Cells

Aldehyde dehydrogenase (ALDH) is a superfamily of enzymes that detoxify a variety of endogenous and exogenous aldehydes and are required for the biosynthesis of retinoic acid (RA) and other molecular regulators of cellular function. Over the past decade, high ALDH activity has been increasingly used as a selectable marker for normal cell populations enriched in stem and progenitor cells, as well as for cell populations from cancer tissues enriched in tumor-initiating stem-like cells. Mounting evidence suggests that ALDH not only may be used as a marker for stem cells but also may well regulate cellular functions related to self-renewal, expansion, differentiation, and resistance to drugs and radiation. ALDH exerts its functional actions partly through RA biosynthesis, as all-trans RA reverses the functional effects of pharmacological inhibition or genetic suppression of ALDH activity in many cell types in vitro. There is substantial evidence to suggest that the role of ALDH as a stem cell marker comes down to the specific isoform(s) expressed in a particular tissue. Much emphasis has been placed on the ALDH1A1 and ALDH1A3 members of the ALDH1 family of cytosolic enzymes required for RA biosynthesis. ALDH1A1 and ALDH1A3 regulate cellular function in both normal stem cells and tumor-initiating stem-like cells, promoting tumor growth and resistance to drugs and radiation. An improved understanding of the molecular mechanisms by which ALDH regulates cellular function will likely open new avenues in many fields, especially in tissue regeneration and oncology.

Role of HMGA2 in human hematopoietic stem and progenitor cells

2013 ◽  
Vol 41 (8) ◽  
pp. S44
Author(s):  
Praveen Kumar ◽  
Aurélie Baudet ◽  
Ineke De Jong ◽  
Jonas Larsson
Keyword(s):  
Progenitor Cells ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

Quantitative Imaging of Femoral Bone Marrow Microenvironments Reveals a Heterogenous Distribution of Hematopoietic Stem and Progenitor Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1455-1455
Author(s):  
Cesar Nombela-Arrieta ◽  
Brendan Harley ◽  
Gregory Pivarnik ◽  
John E Mahoney ◽  
Elena Levantini ◽  
...  
Keyword(s):  
Stem Cells ◽  
B Cells ◽  
Cell Biology ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Quantitative Imaging ◽  
Cell Types ◽  
Immunofluorescent Staining ◽  
Cell Populations ◽  
Hematopoietic Stem

Abstract Abstract 1455 Poster Board I-478 Sustained production of all mature blood cell types relies on the continuous proliferation and differentiation of a rare population of self-renewing, multipotent hematopoietic stem cells (HSCs). HSC maintenance and lineage differentiation are thought to be regulated by spatially confined niches, defined by cellular components, soluble regulators, and the extracellular matrix immediately surrounding stem cells. Identification of these microenvironments in which endogenous and transferred HSCs reside within the BM is a major challenge in stem cell biology with relevant clinical implications. Yet the extreme rarity of HSCs, their dynamic nature, and the lack of specific markers to identify them, have precluded an accurate definition of HSC niches to date. Quantitative imaging technologies such as Laser Scanning Cytometry (LSC) are designed for the automated analysis of large cell numbers at a single cell level with high resolution while preserving the morphological information lost in flow cytometry, therefore providing data of statistical significance even for rare cell populations such as HSCs. We have employed LSC to analyze the localization of both adoptively transferred and endogenous hematopoietic stem and progenitor cell (HSPC) populations inside whole longitudinal sections of murine femoral BM cavities. Our results indicate that, as previously suggested, purified HSPC (Lin−c-kit+Sca-1+) significantly accumulate in endosteal regions (ER) of BM cavities (within 100μm of inner bone surface) upon transplantation. Nevertheless, analysis of sufficient numbers of more differentiated cell subsets (Lin−c-kit+Sca-1− progenitors, pro B cells and mature B cells) indicated that these areas serve as homing sites for most hematopoietic cells, highlighting the limitations of any conclusions drawn on HSC niche identity from studies performed with transferred HSPC populations. Immunofluorescent staining of endogenous cell populations revealed a gradient in distribution of early hematopoietic progenitors (c-kit+), which accumulated in but were not restricted to ER regions. Of note, a vast majority (>80%) of HSPC (Bmi-GFPhic-kit+, or Lin−c-kit+Sca-1+),were found inside ER, although not directly adjacent to endosteal surfaces. Our studies define endosteal areas as tissue regions where HSPC reside in close proximity, but not necessarily in direct contact with a dense vascular network, osteoblastic cells and other potential niche cell types and growth factors currently under investigation. Disclosures No relevant conflicts of interest to declare.

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