scholarly journals Fetal-Derived Immune Cells at the Roots of Lifelong Pathophysiology

2021 ◽  
Vol 9 ◽  
Author(s):  
Elvira Mass ◽  
Rebecca Gentek
Keyword(s):  
Immune Cells ◽  
Innate Immune ◽  
Hematopoietic Stem ◽  
Environmental Perturbations ◽  
Wide Range ◽  
Range Of Functions ◽  
Health And Disease ◽  
Fetal Hematopoiesis ◽  
Early Life Events

Tissue-resident innate immune cells exert a wide range of functions in both adult homeostasis and pathology. Our understanding of when and how these cellular networks are established has dramatically changed with the recognition that many lineages originate at least in part from fetal sources and self-maintain independently from hematopoietic stem cells. Indeed, fetal-derived immune cells are found in most organs and serous cavities of our body, where they reside throughout the entire lifespan. At the same time, there is a growing appreciation that pathologies manifesting in adulthood may be caused by adverse early life events, a concept known as “developmental origins of health and disease” (DOHaD). Yet, whether fetal-derived immune cells are mechanistically involved in DOHaD remains elusive. In this review, we summarize our knowledge of fetal hematopoiesis and its contribution to adult immune compartments, which results in a “layered immune system.” Based on their ontogeny, we argue that fetal-derived immune cells are prime transmitters of long-term consequences of prenatal adversities. In addition to increasing disease susceptibility, these may also directly cause inflammatory, degenerative, and metabolic disorders. We explore this notion for cells generated from erythro-myeloid progenitors (EMP) produced in the extra-embryonic yolk sac. Focusing on macrophages and mast cells, we present emerging evidence implicating them in lifelong disease by either somatic mutations or developmental programming events resulting from maternal and early environmental perturbations.

scholarly journals Early Life Inflammation and the Developing Hematopoietic and Immune Systems: The Cochlea as a Sensitive Indicator of Disruption

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3596
Author(s):  
Kelly S. Otsuka ◽  
Christopher Nielson ◽  
Matthew A. Firpo ◽  
Albert H. Park ◽  
Anna E. Beaudin
Keyword(s):  
Immune Cells ◽  
Early Life ◽  
Congenital Infection ◽  
Perinatal Infection ◽  
Hematopoietic Stem ◽  
Wide Range ◽  
Infection And Inflammation ◽  
Health And Disease ◽  
And Function ◽  
Future Work

Emerging evidence indicates that perinatal infection and inflammation can influence the developing immune system and may ultimately affect long-term health and disease outcomes in offspring by perturbing tissue and immune homeostasis. We posit that perinatal inflammation influences immune outcomes in offspring by perturbing (1) the development and function of fetal-derived immune cells that regulate tissue development and homeostasis, and (2) the establishment and function of developing hematopoietic stem cells (HSCs) that continually generate immune cells across the lifespan. To disentangle the complexities of these interlinked systems, we propose the cochlea as an ideal model tissue to investigate how perinatal infection affects immune, tissue, and stem cell development. The cochlea contains complex tissue architecture and a rich immune milieu that is established during early life. A wide range of congenital infections cause cochlea dysfunction and sensorineural hearing loss (SNHL), likely attributable to early life inflammation. Furthermore, we show that both immune cells and bone marrow hematopoietic progenitors can be simultaneously analyzed within neonatal cochlear samples. Future work investigating the pathogenesis of SNHL in the context of congenital infection will therefore provide critical information on how perinatal inflammation drives disease susceptibility in offspring.

scholarly journals The Role of Cell Metabolism in Innate Immune Memory

2020 ◽  
pp. 1-9
Author(s):  
Anaisa Valido Ferreira ◽  
Jorge Domiguéz-Andrés ◽  
Mihai Gheorghe Netea
Keyword(s):  
Metabolic Pathways ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Innate Immune ◽  
Immune Memory ◽  
Functional Changes ◽  
Trained Immunity ◽  
Health And Disease

Immunological memory is classically attributed to adaptive immune responses, but recent studies have shown that challenged innate immune cells can display long-term functional changes that increase nonspecific responsiveness to subsequent infections. This phenomenon, coined <i>trained immunity</i> or <i>innate immune memory</i>, is based on the epigenetic reprogramming and the rewiring of intracellular metabolic pathways. Here, we review the different metabolic pathways that are modulated in trained immunity. Glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, amino acid, and lipid metabolism are interplaying pathways that are crucial for the establishment of innate immune memory. Unraveling this metabolic wiring allows for a better understanding of innate immune contribution to health and disease. These insights may open avenues for the development of future therapies that aim to harness or dampen the power of the innate immune response.

scholarly journals Activation of the receptor tyrosine kinase RET improves long-term hematopoietic stem cell outgrowth and potency

Blood ◽  
2020 ◽  
Vol 136 (22) ◽  
pp. 2535-2547 ◽  
Author(s):  
W. Grey ◽  
R. Chauhan ◽  
M. Piganeau ◽  
H. Huerga Encabo ◽  
M. Garcia-Albornoz ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Culture Conditions ◽  
Cellular Growth ◽  
Great Promise ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Intracellular Signaling Pathway ◽  
Wide Range

Abstract Expansion of human hematopoietic stem cells (HSCs) is a rapidly advancing field showing great promise for clinical applications. Recent evidence has implicated the nervous system and glial family ligands (GFLs) as potential drivers of hematopoietic survival and self-renewal in the bone marrow niche; how to apply this process to HSC maintenance and expansion has yet to be explored. We show a role for the GFL receptor, RET, at the cell surface of HSCs in mediating sustained cellular growth, resistance to stress, and improved cell survival throughout in vitro expansion. HSCs treated with the key RET ligand/coreceptor complex, glial-derived neurotrophic factor and its coreceptor, exhibit improved progenitor function at primary transplantation and improved long-term HSC function at secondary transplantation. Finally, we show that RET drives a multifaceted intracellular signaling pathway, including key signaling intermediates protein kinase B, extracellular signal-regulated kinase 1/2, NF-κB, and p53, responsible for a wide range of cellular and genetic responses that improve cell growth and survival under culture conditions.

Microglia-Astrocyte Crosstalk: An Intimate Molecular Conversation

2018 ◽  
Vol 25 (3) ◽  
pp. 227-240 ◽  
Author(s):  
Mithilesh Kumar Jha ◽  
Myungjin Jo ◽  
Jae-Hong Kim ◽  
Kyoungho Suk
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Cells ◽  
Tissue Homeostasis ◽  
Reactive Astrocytes ◽  
Innate Immune ◽  
Current Understanding ◽  
Immune Functions ◽  
Health And Disease ◽  
Neuronal Functions

Microglia-astrocyte crosstalk has recently been at the forefront of glial research. Emerging evidence illustrates that microglia- and astrocyte-derived signals are the functional determinants for the fates of astrocytes and microglia, respectively. By releasing diverse signaling molecules, both microglia and astrocytes establish autocrine feedback and their bidirectional conversation for a tight reciprocal modulation during central nervous system (CNS) insult or injury. Microglia, the constant sensors of changes in the CNS microenvironment and restorers of tissue homeostasis, not only serve as the primary immune cells of the CNS but also regulate the innate immune functions of astrocytes. Similarly, microglia determine the functions of reactive astrocytes, ranging from neuroprotective to neurotoxic. Conversely, astrocytes through their secreted molecules regulate microglial phenotypes and functions ranging from motility to phagocytosis. Altogether, the microglia-astrocyte crosstalk is fundamental to neuronal functions and dysfunctions. This review discusses the current understanding of the intimate molecular conversation between microglia and astrocytes and outlines its potential implications in CNS health and disease.

Expressives in Kam (Dong 侗): A study in sign typology (part 11)

2005 ◽  
Vol 34 (1) ◽  
pp. 25-67
Author(s):  
Matthias GERNER
Keyword(s):  
Second Order ◽  
Sound Symbolism ◽  
Wide Range ◽  
Range Of Functions

Like many Austro-Tai languages and many Sino-Tibetan languages, Kam (Dong 侗) exhibits a wealth of descriptive syllables after the verb or the adjective. These syllables, henceforth called expressives, are typically reduplicated and cover a wide range of functions such as grading, speed and manner modification, and various kinds of sound symbolism, metaphor, etc. I propose to view the expressive compound as a sign: the predicate-head functions as the signified and the expressive as the signifier. In fact, since the predicate-head itself has the classical Saussurean sign anatomy, the head-expressive compound presents the case of a complex sign or what I call a second-order sign. The attested types of relationship that hold between the signified and signifier spread across almost the whole spectrum of sign species recognized in the literature. This paper is the result of a survey of ca 260 expressives and is one of the achievements of a long-term Kam dictionary project.

scholarly journals Leukemia Stem Cells as a Potential Target to Achieve Therapy-Free Remission in Chronic Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5822
Author(s):  
Kyoko Ito ◽  
Keisuke Ito
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Drug Binding ◽  
Leukemia Stem Cells ◽  
Phase Point ◽  
Hematopoietic Stem ◽  
Wide Range ◽  
Tki Resistance

Leukemia stem cells (LSCs, also known as leukemia-initiating cells) not only drive leukemia initiation and progression, but also contribute to drug resistance and/or disease relapse. Therefore, eradication of every last LSC is critical for a patient’s long-term cure. Chronic myeloid leukemia (CML) is a myeloproliferative disorder that arises from multipotent hematopoietic stem and progenitor cells. Tyrosine kinase inhibitors (TKIs) have dramatically improved long-term outcomes and quality of life for patients with CML in the chronic phase. Point mutations of the kinase domain of BCR-ABL1 lead to TKI resistance through a reduction in drug binding, and as a result, several new generations of TKIs have been introduced to the clinic. Some patients develop TKI resistance without known mutations, however, and the presence of LSCs is believed to be at least partially associated with resistance development and CML relapse. We previously proposed targeting quiescent LSCs as a therapeutic approach to CML, and a number of potential strategies for targeting insensitive LSCs have been presented over the last decade. The identification of specific markers distinguishing CML-LSCs from healthy HSCs, and the potential contributions of the bone marrow microenvironment to CML pathogenesis, have also been explored. Nonetheless, 25% of CML patients are still expected to switch TKIs at least once, and various TKI discontinuation studies have shown a wide range in the incidence of molecular relapse (from 30% to 60%). In this review, we revisit the current knowledge regarding the role(s) of LSCs in CML leukemogenesis and response to pharmacological treatment and explore how durable treatment-free remission may be achieved and maintained after discontinuing TKI treatment.

scholarly journals Elucidating the Innate Immunological Effects of Mild Magnetic Hyperthermia on U87 Human Glioblastoma Cells: An in vitro Study

2021 ◽  
Author(s):  
Stefano Persano ◽  
Francesco Vicini ◽  
Alessandro Poggi ◽  
Jordi Leonardo Castrillo Fernandez ◽  
Giusy Maria Rita Rizzo ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Magnetic Hyperthermia ◽  
Innate Immune ◽  
Target Cells ◽  
Innate Immune Cells ◽  
Glioblastoma Cells ◽  
Mild Hyperthermia ◽  
Wide Range

Cancer immunotherapies are gaining a large popularity and many of them have been approved as standard second-line or in some cases even as first-line treatment for a wide range of cancers. However, immunotherapy has not shown a clinically relevant success in glioblastoma (GBM), principally due to the brain&rsquo;s &ldquo;immune-privileged&rdquo; status and the peculiar tumor microenvironment (TME) of GBM featured by lack of presence of tumor-infiltrating lymphocytes and the establishment of immunosuppressive mechanisms. Emerging evidence has highlighted the key role played by innate immune cells in immunosurveillance and in initiating and driving immune responses against GBM. Immunogenic cell death (ICD) is a promising approach to elicit direct activation of the innate immune system by inducing in target cancer cells the expression of molecular signatures recognized through a repertoire of innate immune cell pattern recognition receptors (PRRs) by effector innate immune cells. Herein, we explored local mild thermal treatment, generated by using ultrasmall (size ~ 17 nm) cubic-shaped iron oxide nanoparticles exposed to an external alternating magnetic field (AMF), to induce ICD in U87 glioblastoma cells. In accordance with what has been previously observed with other types of tumors, we found that mild hyperthermia modulates the immunological profile of U87 glioblastoma cells by inducing stress-associated signals leading to enhanced phagocytosis and killing of U87 cells by macrophages. Finally, we demonstrated that mild magnetic hyperthermia has a modulatory effect on the expression of inhibitory and activating NK cell ligands on target cells. Interestingly, alteration in the expression of NK ligands, caused by mild hyperthermia treatment, in U87 glioblastoma cells, increased their susceptibility to NK cell killing and NK cell functionality. The overall findings demonstrate that mild magnetic hyperthermia stimulates ICD and sensitizes GBM cells to NK-mediated killing by inducing the upregulation of specific stress ligands, providing a novel immunotherapeutic approach for GBM treatment, with potential to synergize with existing NK cell-based therapies thus improving their therapeutic outcomes.

scholarly journals Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Kristina Berve ◽  
Brian L. West ◽  
Rudolf Martini ◽  
Janos Groh
Keyword(s):  
Visual Acuity ◽  
Immune Cells ◽  
Term Treatment ◽  
Innate Immune ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Innate Immune Cells ◽  
Immune Reactions ◽  
Neuron Loss ◽  
Long Term Treatment

Abstract Background The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1−/−) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mice. Methods We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry. Results We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1−/− mice regarding some histopathological and clinical readouts and reflects heterogeneity of innate immune reactions in the diseased CNS. Conclusions Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.

scholarly journals In situ production of innate immune cells in murine white adipose tissue

Blood ◽  
2012 ◽  
Vol 120 (25) ◽  
pp. 4952-4962 ◽  
Author(s):  
Sandrine Poglio ◽  
Fabienne De Toni ◽  
Daniel Lewandowski ◽  
Adeline Minot ◽  
Emmanuelle Arnaud ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cell Population ◽  
White Adipose Tissue ◽  
Immune Cells ◽  
Immune Cell ◽  
Innate Immune ◽  
Immune Cell Population ◽  
Hematopoietic Stem ◽  
Hematopoietic Activity

Abstract White adipose tissue (WAT) is the focus of new interest because of the presence of an abundant and complex immune cell population that is involved in key pathologies such as metabolic syndrome. Based on in vivo reconstitution assays, it is thought that these immune cells are derived from the bone marrow (BM). However, previous studies have shown that WAT exhibits specific hematopoietic activity exerted by an unknown subpopulation of cells. In the present study, we prospectively isolated a peculiar hematopoietic stem/progenitor cell population from murine WAT. The cells are phenotypically similar to BM hematopoietic stem cells and are able to differentiate into both myeloid and lymphoid lineages in vitro. In competitive repopulation assays in vivo, they reconstituted the innate immune compartment in WAT preferentially and more efficiently than BM cells, but did not reconstitute hematopoietic organs. They were also able to give rise to multilineage engraftment in both secondary recipients and in utero transplantation. Therefore, we propose that WAT hematopoietic cells constitute a population of immature cells that are able to renew innate immune cell populations. Considering the amount of WAT in adults, our results suggest that WAT hematopoietic activity controls WAT inflammatory processes and also supports innate immune responses in other organs.

Tie2Cre-mediated gene ablation defines the stem-cell leukemia gene (SCL/tal1)–dependent window during hematopoietic stem-cell development

Blood ◽  
2005 ◽  
Vol 105 (10) ◽  
pp. 3871-3874 ◽  
Author(s):  
Thorsten M. Schlaeger ◽  
Hanna K. A. Mikkola ◽  
Christos Gekas ◽  
Hildur B. Helgadottir ◽  
Stuart H. Orkin
Keyword(s):  
Stem Cell ◽  
Blood Cells ◽  
Fetal Liver ◽  
Cell Leukemia ◽  
Hematopoietic Stem ◽  
Gene Ablation ◽  
Epidermal Growth ◽  
Fetal Hematopoiesis ◽  
Stem Cell Leukemia

AbstractThe stem-cell leukemia gene (SCL/tal1) is essential for the formation of all blood lineages. SCL is first expressed in mesodermal cells that give rise to embryonic blood cells, and continues to be expressed in fetal and adult hematopoietic stem cells (HSCs). However, SCL is not required for the maintenance of established long-term repopulating (LTR) HSCs in the adult. The time point at which HSC development becomes SCL independent has not been defined. Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains–2 (Tie2) expression appears in hemogenic and vasculogenic sites shortly after SCL. We therefore used the Tie2Cre mouse to inactivate SCL early during embryonic and fetal hematopoiesis. Tie2Cre completely inactivated SCL in yolk sac, the aortagonad-mesonephros (AGM) region, and fetal liver hematopoietic cells and circulating blood cells. However, the fetal liver was colonized by functional LTR-HSCs. Yet SCL remained crucial for proper differentiation of both primitive and definitive red cells and megakaryocytes. These results indicate that the SCL-dependent phase of HSC development ends before Tie2Cre-mediated gene ablation becomes effective.

Sign in / Sign up

Export Citation Format

Share Document