scholarly journals Hematopoietic Stem and Progenitor Cells as Effectors in Innate Immunity

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Jennifer L. Granick ◽  
Scott I. Simon ◽  
Dori L. Borjesson
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Progenitor Cells ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Phenotypic Characterization ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Stem And Progenitor Cells ◽  
And Function

Recent research has shed light on novel functions of hematopoietic stem and progenitor cells (HSPC). While they are critical for maintenance and replenishment of blood cells in the bone marrow, these cells are not limited to the bone marrow compartment and function beyond their role in hematopoiesis. HSPC can leave bone marrow and circulate in peripheral blood and lymph, a process often manipulated therapeutically for the purpose of transplantation. Additionally, these cells preferentially home to extramedullary sites of inflammation where they can differentiate to more mature effector cells. HSPC are susceptible to various pathogens, though they may participate in the innate immune response without being directly infected. They express pattern recognition receptors for detection of endogenous and exogenous danger-associated molecular patterns and respond not only by the formation of daughter cells but can themselves secrete powerful cytokines. This paper summarizes the functional and phenotypic characterization of HSPC, their niche within and outside of the bone marrow, and what is known regarding their role in the innate immune response.

scholarly journals Hematopoietic stem and progenitor cells are present in healthy gingiva tissue

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Siddharth Krishnan ◽  
Kelly Wemyss ◽  
Ian E. Prise ◽  
Flora A. McClure ◽  
Conor O’Boyle ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Responses ◽  
Progenitor Cells ◽  
Myeloid Cell ◽  
Extramedullary Hematopoiesis ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Stem And Progenitor Cells

Hematopoietic stem cells reside in the bone marrow, where they generate the effector cells that drive immune responses. However, in response to inflammation, some hematopoietic stem and progenitor cells (HSPCs) are recruited to tissue sites and undergo extramedullary hematopoiesis. Contrasting with this paradigm, here we show residence and differentiation of HSPCs in healthy gingiva, a key oral barrier in the absence of overt inflammation. We initially defined a population of gingiva monocytes that could be locally maintained; we subsequently identified not only monocyte progenitors but also diverse HSPCs within the gingiva that could give rise to multiple myeloid lineages. Gingiva HSPCs possessed similar differentiation potentials, reconstitution capabilities, and heterogeneity to bone marrow HSPCs. However, gingival HSPCs responded differently to inflammatory insults, responding to oral but not systemic inflammation. Combined, we highlight a novel pathway of myeloid cell development at a healthy barrier, defining a gingiva-specific HSPC network that supports generation of a proportion of the innate immune cells that police this barrier.

Characterization of Hematopoietic Stem Cell Frequency and Function In Unexplained Anemia of the Elderly

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2047-2047
Author(s):  
Wendy Pang ◽  
Elizabeth Price ◽  
Irving L. Weissman ◽  
Stanley L. Schrier
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
In Vitro Culture ◽  
Progenitor Cells ◽  
The Elderly ◽  
Elderly Subjects ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
And Function

Abstract Abstract 2047 Anemia is both a highly prevalent and clinically important condition that causes significant morbidity and mortality in the elderly population. While anemia in the elderly can be attributed to a number of causes, approximately 30% of elderly subjects with anemia have no overt etiology and fall under the category of unexplained anemia of the elderly (UA). There is increasing evidence to suggest that changes in the frequency and/or function of hematopoietic stem and progenitor cells may contribute to the onset and pathophysiology of age-associated hematological conditions, such as UA. Hematopoietic stem cells (HSC) reside at the top of the hematopoietic hierarchy and can differentiate, via increasingly committed downstream progenitors, into all the mature cells of the hematopoietic system. Human myelo-erythroid development proceeds through a set of oligopotent progenitors: HSC give rise to multipotent progenitors (MPP), which give rise to common myeloid progenitors (CMP), which in turn give rise to granulocyte-macrophage progenitors (GMP) and megakaryocyte-erythrocyte progenitors (MEP). We use flow cytometry and in vitro culture of sorted human HSC (Lin-CD34+CD38-CD90+CD45RA-), MPP (Lin-CD34+CD38-CD90-CD45RA-), CMP (Lin-CD34+CD38+CD123+CD45RA-), GMP (Lin-CD34+CD38+CD123+CD45RA+), and MEP (Lin-CD34+CD38+CD123-CD45RA-) from hematologically normal young (23 samples; age 20–35) and elderly (11 samples; age 65+) and UA (5 samples; age 65+) bone marrow samples in order to characterize the changes in the distribution and function of hematopoietic stem and progenitor populations during the aging process and, in particular, in the development of UA. We found that UA patients contain higher frequencies of HSC compared to both elderly normal (1.5-fold; p<0.03) and young normal samples (2.8-fold; p<10-5). We also found increased frequencies of MPP from UA patients compared to MPP from elderly normal (2.6-fold; p<0.002) and young normal samples (5.8-fold; p<0.04). While we observed similar frequencies of CMP among the three groups, we found a notable trend suggesting decreased frequencies of GMP and corresponding increased frequencies of MEP in UA patients. Functionally, HSC from the three groups exhibit statistically insignificant differences in the efficiency of colony formation under the myeloid differentiation-promoting methylcellulose-based in vitro culture conditions; however, on average, HSC from elderly bone marrow samples, regardless of the presence or absence of anemia, tend to form fewer colonies in methylcellulose. Interestingly, HSC from UA patients produce more granulocyte-monocyte (CFU-GM) colonies and fewer erythroid (CFU-E and BFU-E) colonies, compared to HSC from normal samples (p<0.001). Similarly, CMP from UA patients, compared to normal CMP, yield skewed distributions of myeloid-erythroid colonies when plated in methylcellulose, significantly favoring production of CFU-GM colonies over CFU-E and BFU-E colonies (p<0.003). Additionally, MEP from UA patients form both CFU-E and BFU-E colonies in methylcellulose albeit at a significantly lower efficiency than MEP from normal bone marrow samples (p<0.01). This is the first study to examine the changes in hematopoietic stem and progenitor populations in UA patients. The changes in the distribution of hematopoietic stem and progenitor cells in UA patients indicate that the HSC and MPP populations, and possibly also the MEP population, expand in the context of anemia, potentially in response to homeostatic feedback mechanisms. Nevertheless, these expanded populations are functionally impaired in their ability to differentiate towards the erythroid lineage. Our data suggest that there are intrinsic defects in the HSC population of UA patients that lead to poor erythroid differentiation, which can be readily observed even in the earliest committed myelo-erythroid progenitors. We have generated gene expression profiling data from these purified hematopoietic stem and progenitor populations from UA patients to try to identify biological pathways and markers relevant to disease pathogenesis and potential therapeutic targets. Disclosures: Weissman: Amgen, Systemix, Stem cells Inc, Cellerant: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Schrier:Celgene: Research Funding.

scholarly journals Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Bo O Zhou ◽  
Lei Ding ◽  
Sean J Morrison
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Stromal Cells ◽  
Leptin Receptor ◽  
Hematopoietic Cells ◽  
Perivascular Niche ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
And Function ◽  
Angiopoietin 1

Hematopoietic stem cells (HSCs) are maintained by a perivascular niche in bone marrow but it is unclear whether the niche is reciprocally regulated by HSCs. Here, we systematically assessed the expression and function of Angiopoietin-1 (Angpt1) in bone marrow. Angpt1 was not expressed by osteoblasts. Angpt1 was most highly expressed by HSCs, and at lower levels by c-kit+ hematopoietic progenitors, megakaryocytes, and Leptin Receptor+ (LepR+) stromal cells. Global conditional deletion of Angpt1, or deletion from osteoblasts, LepR+ cells, Nes-cre-expressing cells, megakaryocytes, endothelial cells or hematopoietic cells in normal mice did not affect hematopoiesis, HSC maintenance, or HSC quiescence. Deletion of Angpt1 from hematopoietic cells and LepR+ cells had little effect on vasculature or HSC frequency under steady-state conditions but accelerated vascular and hematopoietic recovery after irradiation while increasing vascular leakiness. Hematopoietic stem/progenitor cells and LepR+ stromal cells regulate niche regeneration by secreting Angpt1, reducing vascular leakiness but slowing niche recovery.

scholarly journals Megakaryocytic TGFβ1 Partitions Hematopoiesis into Amplifying Stem and Progenitor Cells and Maturing Effector Cells

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 81-81
Author(s):  
Silvana Di Giandomenico ◽  
Pouneh Kermani ◽  
Nicole Molle ◽  
Mia Yabut ◽  
Fabienne Brenet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Progenitor Cells ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Erythroid Precursors ◽  
Stem And Progenitor Cells

Abstract Background: Chronic anemia is a significant problem affecting over 3 million Americans annually. Therapies are restricted to transfusion and Erythropoietin Stimulating Agents (ESA). There is a need for new approaches to treat chronic anemia. Immature erythroid progenitors are thought to be continuously produced and then permitted to survive and mature if there is sufficient erythropoietin (Epo) available. This model is elegant in that oxygen sensing within the kidney triggers Epo production so anemia can increase Epo and promote erythroid output. However, during homeostasis this model suggests that considerable energy is used to produce unneeded erythroid progenitors. We searched for independent control and compartmentalization of erythropoiesis that could couple early hematopoiesis to terminal erythroid commitment and maturation. Methods: We previously found the proportion of bone marrow megakaryocytes (MKs) staining for active, signaling-competent TGFβ transiently increases during bone marrow regeneration after chemotherapy. To assess the functional role of Mk-TGFβ, we crossed murine strains harboring a floxed allele of TGFβ1 (TGFβ1Flox/Flox) littermate with a Mk-specific Cre deleter to generate mice with Mk-specific deletion of TGFβ1 (TGFβ1ΔMk/ΔMk). We analyzed hematopoiesis of these mice using high-dimensional flow cytometry, confocal immunofluorescent microscopy and in vitro and in vivo assays of hematopoietic function (Colony forming assays, and in vivo transplantation). Results: Using validated, 9-color flow cytometry panels capable of quantifying hematopoietic stem cells (HSCs) and six other hematopoietic progenitor populations, we found that Mk-specific deletion of TGFβ1 leads to expansion of immature hematopoietic stem and progenitor cells (HSPCs) (Fig1A&B). Functional assays confirmed a more than three-fold increase in hematopoietic stem cells (HSCs) capable of serially-transplanting syngeneic recipients in the bone marrow (BM) of TGFβ1ΔMk/ΔMk mice compared to their TGFβ1Flox/Flox littermates. Expansion was associated with less quiescent (Go) HSCs implicating Mk-TGFβ in the control of HSC cell cycle entry. Similarly, in vitro colony forming cell assays and in vivo spleen colony forming assays confirmed expansion of functional progenitor cells in TGFβ1ΔMk/ΔMk mice. These results place Mk-TGFβ as a critical regulator of the size of the pool of immature HSPCs. We found that the blood counts and total BM cellularity of TGFβ1ΔMk/ΔMk mice was normal despite the dramatic expansion of immature HSPCs. Using a combination of confocal immunofluorescence microscopy (cleaved caspase 3) (Fig1C) and flow cytometry (Annexin V and cleaved caspase 3) (Fig1D), we found ~10-fold greater apoptosis of mature precursor cells in TGFβ1ΔMk/ΔMk BM and spleens. Coincident with this, we found the number of Epo receptor (EpoR) expressing erythroid precursors to be dramatically increased. Indeed, apoptosis of erythroid precursors peaked as they transitioned from dual positive Kit+EpoR+ precursors to single positive cells expressing EpoR alone. Epo levels were normal in the serum of these mice. We reasoned that the excess, unneeded EpoR+ cells were not supported physiologic Epo levels but might respond to even small doses of exogenous Epo. Indeed, we found that the excess erythroid apoptosis could be rescued by administration of very low doses of Epo (Fig1E). Whereas TGFβ1Flox/Flox mice showed minimal reticulocytosis and no change in blood counts, TGFβ1ΔMk/ΔMk mice responded with exuberant reticulocytosis and raised RBC counts almost 10% within 6 days (Fig. 1F). Low dose Epo also rescued survival of Epo receptor positive erythroid precursors in the bone marrow, spleen and blood of TGFβ1ΔMk/ΔMk mice. TGFβ1ΔMk/ΔMk mice showed a similarly brisk and robust erythropoietic response during recovery from phenylhydrazine-induced hemolysis (Fig.1G). Exogenous TGFβ worsened BM apoptosis and caused anemia in treated mice. Pre-treatment of wild-type mice with a TGFβ signaling inhibitor sensitized mice to low dose Epo. Conclusion: These results place megakaryocytic TGFβ1 as a gate-keeper that restricts the pool of immature HSPCs and couples immature hematopoiesis to the production of mature effector cells. This work promises new therapies for chronic anemias by combining TGFβ inhibitors to increase the outflow of immature progenitors with ESAs to support erythroid maturation. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Microbial Impact on Hematologic Homeostasis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-40-SCI-40
Author(s):  
Markus G. Manz
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Immune Cells ◽  
Proliferative Potential ◽  
Ongoing Research ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Enhanced Production ◽  
Stem And Progenitor Cells ◽  
And Migration

Abstract Abstract SCI-40 During systemic infection and inflammation, immune effector cells are in high demand and are rapidly consumed at sites of need. While adaptive immune cells have high proliferative potential, innate mature immune cells are mostly postmitotic and need to be replenished from bone marrow hematopoietic stem and progenitor cells. Indeed, severe clinical infection, particularly infections challenging the innate immune response, lead to an increase in hematopoietic differentiation and throughput in bone marrow, involving subsequent differentiation stages from hematopoietic stem cells, multipotent progenitors, as well as early-lineage and late-lineage restricted hematopoietic progenitors. A fundamental question is how the increased need is sensed and translated in enhanced production and how adequate levels of response are guided. Recent research has shed light on conserved intracellular and extracellular pathogen recognition receptors, such as Toll-like receptors, that are expressed on nonhematopoietic and hematopoietic effector cells and cause activation upon ligation. This activation results in production of hematopoietic growth, survival, activation, and migration factors operating at site on effector cells, but also at remote primary hematopoietic sites to increase production upon need. Recent research by several groups, including ours, surprisingly revealed that conserved pattern-recognition receptors are also expressed on hematopoietic stem and progenitor cells in bone marrow, implying a direct effect of systemically available ligands on these cellular populations. Indeed, it has been demonstrated that, for example, ligation of Toll-like receptor 4 by its cognate agonist lipopolysaccharide can lead to divisional activation, proliferation, lineage-directed differentiation, and migration of hematopoietic stem and lineage-restricted progenitor cells, all aimed at efficient contribution to immune responses and rapid reestablishment of hematopoietic homeostasis. The relative contribution of pathogen sensing by hematopoietic and diverse nonhematopoietic cells to appropriate hematopoietic responses, as well as the subcellular translation of the signals, is the focus of ongoing research. Also to be discussed will be how chronic infectious and inflammatory processes, which are frequently associated with aging, might impinge on hematopoiesis, potentially fostering hematopoietic stem cell diseases as exhaustion or transformation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cooperating Effect of Rps14, Csnk1a1 and miRNA145/miRNA146a Haploinsufficiency in the Activation of the Innate Immune System in Del(5q) MDS

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 356-356
Author(s):  
Schneider K. Rebekka ◽  
Monica Schenone ◽  
Monica Ferreira Ventura ◽  
Fabian Beier ◽  
Tim H. Bruemmendorf ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Research Funding ◽  
Erythroid Differentiation ◽  
Innate Immune ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Innate Immune Signaling ◽  
Stem And Progenitor Cells ◽  
Cell Type Specific

Abstract Heterozygous deletion of RPS14 occurs in del(5q) MDS and has been linked to impaired erythropoiesis, characteristic of this disease subtype. We previously generated a mouse model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age-dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence. We now sought to determine the mechanistic basis for the anemia using unbiased, quantitative mass spectrometry in erythroid progenitor cells. We found powerful induction of proteins involved in innate immune signaling, particularly the danger associated molecular pattern (DAMP) heterodimeric S100A8/S100A9 proteins. We found significantly increased S100a8 in the erythroid progenitor populations affected by the differentiation block (RIII-RIV population) and in monocytes and macrophages of Rps14 haploinsufficient bone marrows, all representing cells of the erythroblastic niche. Recombinant S100A8 was sufficient to impair erythropoiesis in wild-type cells. We rescued the erythroid differentiation defect in Rps14 haploinsufficient HSCs by genetic inactivation of S100a8 expression using CRISPR/Cas-mediated gene inactivation in primary mouse Rps14 haploinsufficient HSPC. We validated the association between induction of S100A8 and a severe erythroid phenotype in bone marrow samples of patients with del(5q) MDS. To examine whether ribosomal haploinsufficiency also leads to activation of S100A8 in patients with del(5q) MDS, we measured S100A8 expression using immunofluorescence in bone marrow biopsies from MDS patients with and without del(5q). In del(5q) MDS, the frequency of S100A8-positive cells was associated with disease severity, as reflected by transfusion burden. RPS14, CSNK1A1 and miR-145 are universally co-deleted in the 5q- syndrome and each represent different clinical features of del(5q) MDS in murine models. Haploinsufficiency of miR-145 or -146a also induces inappropriate activation of innate immune signaling. To analyze the combinatorial effect of haploinsufficiency Rps14, Csnk1a1 and miRNA-145, we transduced hematopoietic stem and progenitor cells (HSPC) from compound haploinsufficient Rps14 and Csnk1a1 mice and stably knocked down both miR-145/miR-146a by retrovirus-mediated overexpression of respective target sequences. Compound haploinsufficiency of Rps14, Csnk1a1 and miR-145/146a led to a progressive anemia comparable to Rps14 haploinsufficiency with splenomegaly and an erythroid differentiation defect at the RIII/RIV population, indicating that the anemia is mainly driven by Rps14 haploinsufficiency. Bone marrow histology demonstrated the typical 5q-phenoytpe of megakaryocytes, in line with significant thrombocytosis. At 10 months of age, hematopoietic stem and progenitor cells were significantly increased (lineagelow ckit+ Sca1+; LSK), in particular multipotent progenitor cells (MPPs; lineagelow ckit+ Sca1+ CD48- CD150+) to significantly higher extents than in solely Rps14 or Csnk1a1 haploinsufficient cells. We next asked if compound haploinsufficiency of the three 5q-genes has combinatorial or synergistic effects on S100a8 expression. Compound haploinsufficiency of Csnk1a1, Rps14 and miR-145/146a induced the highest expression of S100a8 in monocytes, while haploinsufficiency of Rps14 alone induced the highest expression of S100a8 in the RIII erythroid population, suggesting that cell-type specific induction mediates the phenotype. Our data indicate an unexpected link between haploinsufficiency for a ribosomal gene, Rps14, activation of S100A8, and inhibition of erythropoiesis. We demonstrate that compound haploinsufficiency for Csnk1a1 and miR145/146a with Rps14 haploinsuffciency increases the expression of S100a8, mainly in monocytes, and recapitulates the phenotype of del(5q) MDS by cooperating, cell-type specific effects. Disclosures Platzbecker: Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Boehringer: Research Funding.

3008 – OXYGEN TENSION REGULATES CALCIUM SIGNALING AND FUNCTION IN HEMATOPOIETIC STEM AND PROGENITOR CELLS

2020 ◽  
Vol 88 ◽  
pp. S40
Author(s):  
Paige Dausinas ◽  
Jacob Slack ◽  
Christopher Basile ◽  
Anish Karlapudi ◽  
Heather O'Leary
Keyword(s):  
Calcium Signaling ◽  
Progenitor Cells ◽  
Oxygen Tension ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
And Function

scholarly journals Mechanism of Action of Diallyl Sulphide in Ameliorating the Hematopoietic Radiation Injury

2021 ◽  
Author(s):  
Omika Katoch ◽  
Mrinalini Tiwari ◽  
Namita Kalra ◽  
Paban K. Agrawala
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Progenitor Cells ◽  
Hematopoietic Stem ◽  
Proliferation And Differentiation ◽  
Stem And Progenitor Cells ◽  
Radiation Induced ◽  
Medicinal Properties ◽  
Marrow Cellularity

AbstractDiallyl sulphide (DAS), the pungent component of garlic, is known to have several medicinal properties and has recently been shown to have radiomitigative properties. The present study was performed to better understand its mode of action in rendering radiomitigation. Evaluation of the colonogenic ability of hematopoietic progenitor cells (HPCs) on methocult media, proliferation and differentiation of hematopoietic stem cells (HSCs), and transplantation of stem cells were performed. The supporting tissue of HSCs was also evaluated by examining the histology of bone marrow and in vitro colony-forming unit–fibroblast (CFU-F) count. Alterations in the levels of IL-5, IL-6 and COX-2 were studied as a function of radiation or DAS treatment. It was observed that an increase in proliferation and differentiation of hematopoietic stem and progenitor cells occurred by postirradiation DAS administration. It also resulted in increased circulating and bone marrow homing of transplanted stem cells. Enhancement in bone marrow cellularity, CFU-F count, and cytokine IL-5 level were also evident. All those actions of DAS that could possibly add to its radiomitigative potential and can be attributed to its HDAC inhibitory properties, as was observed by the reversal radiation induced increase in histone acetylation.

Sign in / Sign up

Export Citation Format

Share Document