scholarly journals Hematopoiesis: A Layered Organization Across Chordate Species

2020 ◽  
Vol 8 ◽  
Author(s):  
Ramy Elsaid ◽  
Francisca Soares-da-Silva ◽  
Marcia Peixoto ◽  
Dali Amiri ◽  
Nathan Mackowski ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Immune Cells ◽  
Single Cells ◽  
Cell Types ◽  
Tissue Homeostasis ◽  
Lymphoid Cells ◽  
Specific Cell ◽  
Hematopoietic Stem ◽  
Hematopoietic System

The identification of distinct waves of progenitors during development, each corresponding to a specific time, space, and function, provided the basis for the concept of a “layered” organization in development. The concept of a layered hematopoiesis was established by classical embryology studies in birds and amphibians. Recent progress in generating reliable lineage tracing models together with transcriptional and proteomic analyses in single cells revealed that, also in mammals, the hematopoietic system evolves in successive waves of progenitors with distinct properties and fate. During embryogenesis, sequential waves of hematopoietic progenitors emerge at different anatomic sites, generating specific cell types with distinct functions and tissue homing capacities. The first progenitors originate in the yolk sac before the emergence of hematopoietic stem cells, some giving rise to progenies that persist throughout life. Hematopoietic stem cell-derived cells that protect organisms against environmental pathogens follow the same sequential strategy, with subsets of lymphoid cells being only produced during embryonic development. Growing evidence indicates that fetal immune cells contribute to the proper development of the organs they seed and later ensure life-long tissue homeostasis and immune protection. They include macrophages, mast cells, some γδ T cells, B-1 B cells, and innate lymphoid cells, which have “non-redundant” functions, and early perturbations in their development or function affect immunity in the adult. These observations challenged the view that all hematopoietic cells found in the adult result from constant and monotonous production from bone marrow-resident hematopoietic stem cells. In this review, we evaluate evidence for a layered hematopoietic system across species. We discuss mechanisms and selective pressures leading to the temporal generation of different cell types. We elaborate on the consequences of disturbing fetal immune cells on tissue homeostasis and immune development later in life.

The Liver Can Host Donor Hematopoiesis and Maintains a Strong Population of Innate Immune Cells That Contributes to Host Protection After Transplantation of Purified Hematopoietic Stem Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3545-3545
Author(s):  
Pelu Tran ◽  
Antonia MS Mueller ◽  
Judith Shizuru
Keyword(s):  
Stem Cells ◽  
Innate Immunity ◽  
T Cells ◽  
Hematopoietic Stem Cells ◽  
Nk Cells ◽  
Immune Cells ◽  
Lymphoid Cells ◽  
Hematopoietic Stem ◽  
Host Protection

Abstract Abstract 3545 Poster Board III-482 Standing in the line of first defense, the liver is a critical immunocompetent organ. It is armed with lymphocytes, including T cells (TC), natural killer (NK) cells, NK T cells, and a variety of antigen-presenting cells (APC), such as dendritic cells and resident macrophages (Mph), called Kupffer cells. Because it is exposed to large amounts of toxins and antigens, both destructive and harmless, liver immunity must provide immunogenic and tolerogenic mechanisms. Moreover, as the organ of fetal blood production the liver can, if required, resume its hematopoietic function. Here, we studied the role of the liver as a hematopoietic and lymphatic organ after hematopoietic cell transplantation (HCT). Lethally irradiated BALB.K and BALB.B mice were given MHC-matched, FACS purified hematopoietic stem cells (HSC; cKit+Sca1+Thy1.1loLin-) from AKR/J and C57BL/6 donors, respectively, alone or supplemented with 10∧7 splenocytes (SP) for GVHD induction. Mononuclear cells (MNC) were Ficoll-separated from flushed livers 1 to 6 weeks (w) post transplant (pTX) and FACS analyzed. In recipients of TC-containing grafts, the liver was a major target organ of acute graft-vs-host disease (GVHD) with prominent donor lymphocyte expansion causing destruction of the hepatic portal morphology. Rare HSC-derived cells were observed in the livers. In contrast, mice given purified HSC showed no clinical or histological signs of GVHD, yet early pTX a high proportion of donor HSC-derived MNC was observed within the livers, comprising ∼75% of the MNC at 2w. Phenotype analysis revealed that these HSC-derived MNC were primarily NK cells (DX5+CD122+) or Mph (Mac1+F4/80+). In fact, amongst all nucleated cells, NK cells represented >10% and were mixed donor/host type. Interestingly, the Mph were all donor derived. This observation of over-representation by cells of innate immunity (including NK cells and Mph) in livers of recipients of HSC alone led us to hypothesize that these cells might exert protective functions against increased amounts of pathogens and toxins entering the circulation from irradiation-damaged intestines. Thus, to suppress donor Mph reconstitution pTX, silica was injected intraperitoneally on d-1, and every 3d thereafter. All recipients of HSC alone recovered rapidly after irradiation (d5-7), while at this time point recipients of HSC plus silica showed severe weight loss, hunched posture, ruffled fur, diarrhea, with <50% (7/15) survival. These survivors clinically stabilized around d12, suggesting that the intestines recovered from injury. To test if the presence of the HSC derived NK cells and APC could contribute to host protection from GVHD, a lethal dose of SP (10∧7) was injected simultaneously with HSC, or with a delay of 7d or 9d. All mice given SP on d0 died within 9d and 3/5 of those receiving SP on d7 died by d12. However, all mice given SP on d9 recovered fully and showed no signs of GVHD, despite the lymphopenic host environment that usually promotes homeostatic expansion of mature donor TC. In conclusion, the role of the liver as an immunologically active organ after ‘conventional’ HCT is often masked by donor TC expansion with subsequent GVHD. Here, we provide evidence that if grafts are devoid of mature lymphoid cells, innate immunity recovers rapidly, and in fact exceeds unmanipulated controls. Donor Mph may protect the host from pathogens and endotoxemia. Moreover, they may neutralize activated donor TC and thereby mediate tolerance between donor and host. Likewise, the elevated proportion of donor and host NK cells, which is lacking in GVHD affected mice, suggest another beneficial mechanism of protection, as NK cells have been reported to be capable of reducing GVHD. Immunohistochemical studies for a better quantitative assessment of resident immune cells in the liver pTX are underway. Disclosures: No relevant conflicts of interest to declare.

scholarly journals What do we know about the participation of hematopoietic stem cells in hematopoiesis?

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1177 ◽  
Author(s):  
Nina Drize ◽  
Nataliya Petinati
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Types ◽  
Proliferative Potential ◽  
Mature Cell ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
The Past ◽  
Adult Tissues

The demonstrated presence in adult tissues of cells with sustained tissue regenerative potential has given rise to the concept of tissue stem cells. Assays to detect and measure such cells indicate that they have enormous proliferative potential and usually an ability to produce all or many of the mature cell types that define the specialized functionality of the tissue. In the hematopoietic system, one or only a few cells can restore lifelong hematopoiesis of the whole organism. To what extent is the maintenance of hematopoietic stem cells required during normal hematopoiesis? How does the constant maintenance of hematopoiesis occur and what is the behavior of the hematopoietic stem cells in the normal organism? How many of the hematopoietic stem cells are created during the development of the organism? How many hematopoietic stem cells are generating more mature progeny at any given moment? What happens to the population of hematopoietic stem cells in aging? This review will attempt to describe the results of recent research which contradict some of the ideas established over the past 30 years about how hematopoiesis is regulated.

The Impact of Age and Gender on Hematopoietic Stem Cells and Immune Contexture of the Bone Marrow Microenvironment

2020 ◽  
pp. 1-6
Author(s):  
Rebar N. Mohammed
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Immune Cells ◽  
Absolute Number ◽  
Cell Number ◽  
Hematopoietic Stem ◽  
The Absolute ◽  
And Gender ◽  
The Impact

Hematopoietic stem cells (HSCs) are a rare population of cells that reside mainly in the bone marrow and are capable of generating and fulfilling the entire hematopoietic system upon differentiation. Thirty-six healthy donors, attending the HSCT center to donate their bone marrow, were categorized according to their age into child (0–12 years), adolescence (13–18 years), and adult (19–59 years) groups, and gender into male and female groups. Then, the absolute number of HSCs and mature immune cells in their harvested bone marrow was investigated. Here, we report that the absolute cell number can vary considerably based on the age of the healthy donor, and the number of both HSCs and immune cells declines with advancing age. The gender of the donor (male or female) did not have any impact on the number of the HSCs and immune cells in the bone marrow. In conclusion, since the number of HSCs plays a pivotal role in the clinical outcome of allogeneic HSC transplantations, identifying a younger donor regardless the gender is critical.

scholarly journals Histone Acetyltransferases and Stem Cell Identity

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2407
Author(s):  
Ruicen He ◽  
Arthur Dantas ◽  
Karl Riabowol
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Epigenetic Modification ◽  
Cell Types ◽  
Histone Acetyltransferases ◽  
Specific Cell ◽  
Cell Fates ◽  
Cell Identity ◽  
Hematopoietic Stem

Acetylation of histones is a key epigenetic modification involved in transcriptional regulation. The addition of acetyl groups to histone tails generally reduces histone-DNA interactions in the nucleosome leading to increased accessibility for transcription factors and core transcriptional machinery to bind their target sequences. There are approximately 30 histone acetyltransferases and their corresponding complexes, each of which affect the expression of a subset of genes. Because cell identity is determined by gene expression profile, it is unsurprising that the HATs responsible for inducing expression of these genes play a crucial role in determining cell fate. Here, we explore the role of HATs in the maintenance and differentiation of various stem cell types. Several HAT complexes have been characterized to play an important role in activating genes that allow stem cells to self-renew. Knockdown or loss of their activity leads to reduced expression and or differentiation while particular HATs drive differentiation towards specific cell fates. In this study we review functions of the HAT complexes active in pluripotent stem cells, hematopoietic stem cells, muscle satellite cells, mesenchymal stem cells, neural stem cells, and cancer stem cells.

scholarly journals Eradication of HIV by Transplantation of CCR5-Deficient Hematopoietic Stem Cells

2011 ◽  
Vol 11 ◽  
pp. 1068-1076 ◽  
Author(s):  
Gero Hütter ◽  
Susanne Ganepola
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Treatment Strategies ◽  
Allogeneic Transplantation ◽  
Lymphoid Cells ◽  
Natural Resistance ◽  
Tissue Samples ◽  
Hematopoietic Stem ◽  
Open Questions ◽  
Clinical Consequences

Today, 30 years after the onset of the HIV pandemic, although treatment strategies have considerably improved, there is still no cure for the disease. Recently, we described a successful hematopoietic stem cell transplantation in an HIV-1–infected patient, transferring donor-derived cells with a natural resistance against HIV infection. These hematopoietic stem cells engrafted, proliferated, and differentiated into mature myeloid and lymphoid cells. To date, the patient has not required any antiretroviral treatment, more than 4 years after allogeneic transplantation. In the analysis of peripheral blood cells and different tissue samples, including gut, liver, and brain, no viral load or proviral DNA could be detected. Our report raises the hope for further targeted treatment strategies against HIV and represents a successful personalized treatment with allogeneic stem cells carrying a beneficial gene. However, this case has ignited a controversy regarding the question of whether this patient has achieved complete eradication of HIV or not. Here we give an update on open questions, unsolved aspects, and clinical consequences concerning this unique case.

scholarly journals Dissecting the Immune Cell Progeny of CAR-Expressing Hematopoietic Stem Cells in a Humanized Mouse Model

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4640-4640
Author(s):  
Heng-Yi Liu ◽  
Nezia Rahman ◽  
Tzu-Ting Chiou ◽  
Satiro N. De Oliveira
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
T Cell ◽  
Hematopoietic Stem Cells ◽  
Cell Lines ◽  
Immune Cells ◽  
Research Funding ◽  
Humanized Mice ◽  
Tumor Challenge ◽  
Hematopoietic Stem

Background: Chemotherapy-refractory or recurrent B-lineage leukemias and lymphomas yield less than 50% of chance of cure. Therapy with autologous T-cells expressing chimeric antigen receptors (CAR) have led to complete remissions, but the effector cells may not persist, limiting clinical efficacy. Our hypothesis is the modification of hematopoietic stem cells (HSC) with anti-CD19 CAR will lead to persistent generation of multilineage target-specific immune cells, enhancing graft-versus-cancer activity and leading to development of immunological memory. Design/Methods: We generated second-generation CD28- and 4-1BB-costimulated CD19-specific CAR constructs using third-generation lentiviral vectors for modification of human HSC for assessment in vivo in NSG mice engrafted neonatally with human CD34-positive cells. Cells were harvested from bone marrows, spleens, thymus and peripheral blood at different time points for evaluation by flow cytometry and ddPCR for vector copy numbers. Cohorts of mice received tumor challenge with subcutaneous injection of lymphoma cell lines. Results: Gene modification of HSC with CD19-specific CAR did not impair differentiation or proliferation in humanized mice, leading to CAR-expressing cell progeny in myeloid, NK and T-cells. Humanized NSG engrafted with CAR-modified HSC presented similar humanization rates to non-modified HSC, with multilineage CAR-expressing cells present in all tissues with stable levels up to 44 weeks post-transplant. No animals engrafted with CAR-modified HSC presented autoimmunity or inflammation. T-cell populations were identified at higher rates in humanized mice with CAR-modified HSC in comparison to mice engrafted with non-modified HSC. CAR-modified HSC led to development of T-cell effector memory and T-cell central memory phenotypes, confirming the development of long-lasting phenotypes due to directed antigen specificity. Mice engrafted with CAR-modified HSC successfully presented tumor growth inhibition and survival advantage at tumor challenge with lymphoma cell lines, with no difference between both constructs (62.5% survival for CD28-costimulated CAR and 66.6% for 41BB-costimulated CAR). In mice sacrificed due to tumor development, survival post-tumor injection was directly correlated with tumor infiltration by CAR T-cells. Conclusions: CAR modification of human HSC for cancer immunotherapy is feasible and continuously generates CAR-bearing cells in multiple lineages of immune cells. Targeting of different malignancies can be achieved by adjusting target specificity, and this approach can augment the anti-lymphoma activity in autologous HSC recipients. It bears decreased morbidity and mortality and offers alternative therapeutic approach for patients with no available sources for allogeneic transplantation, benefiting ethnic minorities. Disclosures De Oliveira: National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London: Research Funding; NIAID, NHI: Research Funding; Medical Research Council: Research Funding; CIRM: Research Funding; National Gene Vector Repository: Research Funding.

scholarly journals B-1 lymphoid cells develop independently of Notch signaling during mouse embryonic development

2020 ◽  
Author(s):  
Nathalia Azevedo ◽  
Elisa Bertesago ◽  
Ismail Ismailoglu ◽  
Michael Kyba ◽  
Michihiro Kobayashi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Development ◽  
Blood Cell ◽  
Notch Signaling ◽  
Embryonic Stem ◽  
Cell Types ◽  
Lymphoid Cells ◽  
Lineage Specification ◽  
Hematopoietic Stem

AbstractThe in vitro generation from pluripotent stem cells (PSCs) of different blood cell types, in particular those that are not replenished by hematopoietic stem cells (HSCs) like fetal-derived tissue-resident macrophages and innate-like lymphocytes, is of a particular interest. In order to succeed in this endeavor, a thorough understanding of the pathway interplay promoting lineage specification for the different blood cell types is needed. Notch signaling is essential for the HSC generation and their derivatives, but its requirement for tissue-resident immune cells is unknown. Using mouse embryonic stem cells (mESCs) to recapitulate murine embryonic development, we have studied the requirement for Notch signaling during the earliest B-lymphopoiesis and found that Rbpj-deficient mESCs are able to generate B-1 cells. Their Notch-independence was confirmed in ex vivo experiments using Rbpj-deficient embryos. In addition, we found that upregulation of Notch signaling was needed for the emergence of B-2 lymphoid cells. Taken together, these findings indicate that control of Notch signaling dosage is critical for the different B-cell lineage specification and provides pivotal information for their in vitro generation from PSCs for therapeutic applications.

scholarly journals Deletion of PI3-Kinase Promotes Myelodysplasia Through Dysregulation of Autophagy in Hematopoietic Stem Cells

2020 ◽  
Author(s):  
Kristina Ames ◽  
Imit Kaur ◽  
Yang Shi ◽  
Meng Tong ◽  
Taneisha Sinclair ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Akt Pathway ◽  
Hematopoietic Growth Factors ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Phosphoinositide 3 Kinase

AbstractHematopoietic stem cells (HSCs) maintain the blood system through a delicate equilibrium between self-renewal and differentiation. Most hematopoietic growth factors and cytokines signal through phosphoinositide 3-kinase (PI3K) via three Class IA catalytic PI3K isoforms (P110α, β, and δ), encoded by Pik3ca, Pik3cb, and Pik3cd, respectively. The PI3K/AKT pathway is commonly activated in acute myeloid leukemia (AML), and PI3K is a common therapeutic target in cancer. However, it is not known whether PI3K is required for HSC differentiation or self-renewal. We previously demonstrated that individual PI3K isoforms are dispensable in HSCs1,2. To determine the redundant roles of PI3K isoforms in HSCs, we generated a triple knockout (TKO) mouse model with deletion of all three Class IA PI3K isoforms in the hematopoietic system. Surprisingly, we observed significant expansion of TKO HSCs after transplantation, with decreased differentiation capacity and impaired multilineage repopulation. Additionally, the bone marrow of TKO mice exhibited myelodysplastic features with chromosomal abnormalities. Interestingly, we found that macroautophagy (thereafter autophagy) is impaired in TKO HSCs, and that pharmacologic induction of autophagy improves their differentiation. Therefore, we have uncovered important roles for PI3K in autophagy regulation in HSCs to maintain the balance between self-renewal and differentiation.

Haploinsufficiency of AML1 results in a decrease in the number of LTR-HSCs while simultaneously inducing an increase in more mature progenitors

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3565-3572 ◽  
Author(s):  
Weili Sun ◽  
James R. Downing
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Normal Limits ◽  
Platelet Disorder ◽  
Familial Platelet Disorder ◽  
Transcriptional Complex

The AML1/CBFβ transcriptional complex is essential for the formation of definitive hematopoietic stem cells (HSCs). Moreover, development of the hematopoietic system is exquisitely sensitive to the level of this complex. To investigate the effect of AML1 dosage on adult hematopoiesis, we compared the hematopoietic systems of AML1+/– and AML1+/+ mice. Surprisingly, loss of a single AML1 allele resulted in a 50% reduction in long-term repopulating hematopoietic stem cells (LTR-HSCs). This decrease did not, however, extend to the next level of hematopoietic differentiation. Instead, AML1+/– mice had an increase in multilineage progenitors, an expansion that resulted in enhanced engraftment following transplantation. The expanded pool of AML1+/– progenitors remained responsive to homeostatic mechanisms and thus the number of mature cells in most lineages remained within normal limits. Two notable exceptions were a decrease in CD4+ T cells, leading to an inversion of the CD4+ to CD8+ T-cell ratio and a decrease in circulating platelets. These data demonstrate a dosage-dependent role for AML1/CBFβ in regulating the quantity of HSCs and their downstream committed progenitors, as well as a more restricted role in T cells and platelets. The latter defect mimics one of the key abnormalities in human patients with the familial platelet disorder resulting from AML1 haploinsufficiency.

scholarly journals Blood and Cancer: Cancer Stem Cells as Origin of Hematopoietic Cells in Solid Tumor Microenvironments

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1293 ◽  
Author(s):  
Ghmkin Hassan ◽  
Masaharu Seno
Keyword(s):  
Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cancer Cells ◽  
Solid Tumor ◽  
Immune Cells ◽  
Hematopoietic Cells ◽  
Hematopoietic Stem ◽  
Tumor Microenvironments

The concepts of hematopoiesis and the generation of blood and immune cells from hematopoietic stem cells are some steady concepts in the field of hematology. However, the knowledge of hematopoietic cells arising from solid tumor cancer stem cells is novel. In the solid tumor microenvironment, hematopoietic cells play pivotal roles in tumor growth and progression. Recent studies have reported that solid tumor cancer cells or cancer stem cells could differentiate into hematopoietic cells. Here, we discuss efforts and research that focused on the presence of hematopoietic cells in tumor microenvironments. We also discuss hematopoiesis from solid tumor cancer stem cells and clarify the notion of differentiation of solid tumor cancer stem cells into non-cancer hematopoietic stem cells.

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