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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(5): 1690-1694, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34627464

RESUMO

Hematopoietic stem cells (HSCs) reside at the top of the hierarchy and have the ability to differentiate to variety of hematopoietic progenitor cells (HPCs) or mature hematopoietic cells in each system. At present, the procress of HSC and HPC differentiating to the complete hematopoietic system under physiological and stressed conditions is poorly understood. In vivo lineage tracing is a powerful technique that can mark the individual cells and identify the differentiation pathways of their daughter cells, it takes as a strong technical system to research HSC. Traditional lineage tracing studies mainly rely on imaging techniques with fluorescent dyes and nucleic acid analogs. Recently, newly cell tracing technologies have been invented, and the combination of clonal tracing and DNAsequencing technologies have provided a new perspective on cell state, cell fate, and lineage commitment at the single cell level. In this review, these new tracing methods were introduce and discuss, and their advantages over traditional methods in the study of hematopoiesis were summarized briefly.


Assuntos
Hematopoese , Células-Tronco Hematopoéticas , Diferenciação Celular
2.
Stem Cell Res Ther ; 12(1): 528, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620229

RESUMO

BACKGROUND: Current understanding of hematopoiesis is largely derived from mouse models that are physiologically distant from humans. Humanized mice provide the most physiologically relevant small animal model to study human diseases, most notably preclinical gene therapy studies. However, the clonal repopulation dynamics of human hematopoietic stem and progenitor cells (HSPC) in these animal models is only partially understood. Using a new clonal tracking methodology designed for small sample volumes, we aim to reveal the underlying clonal dynamics of human cell repopulation in a mouse environment. METHODS: Humanized bone marrow-liver-thymus (hu-BLT) mice were generated by transplanting lentiviral vector-transduced human fetal liver HSPC (FL-HSPC) in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice implanted with a piece of human fetal thymus. We developed a methodology to track vector integration sites (VIS) in a mere 25 µl of mouse blood for longitudinal and quantitative clonal analysis of human HSPC repopulation in mouse environment. We explored transcriptional and epigenetic features of human HSPC for possible VIS bias. RESULTS: A total of 897 HSPC clones were longitudinally tracked in hu-BLT mice-providing a first-ever demonstration of clonal dynamics and coordinated expansion of therapeutic and control vector-modified human cell populations simultaneously repopulating in the same humanized mice. The polyclonal repopulation stabilized at 19 weeks post-transplant and the contribution of the largest clone doubled within 4 weeks. Moreover, 550 (~ 60%) clones persisted over 6 weeks and were highly shared between different organs. The normal clonal profiles confirmed the safety of our gene therapy vectors. Multi-omics analysis of human FL-HSPC revealed that 54% of vector integrations in repopulating clones occurred within ± 1 kb of H3K36me3-enriched regions. CONCLUSIONS: Human repopulation in mice is polyclonal and stabilizes more rapidly than that previously observed in humans. VIS preference for H3K36me3 has no apparent negative effects on HSPC repopulation. Our study provides a methodology to longitudinally track clonal repopulation in small animal models extensively used for stem cell and gene therapy research and with lentiviral vectors designed for clinical applications. Results of this study provide a framework for understanding the clonal behavior of human HPSC repopulating in a mouse environment, critical for translating results from humanized mice models to the human settings.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Animais , Modelos Animais de Doenças , Hematopoese , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
3.
Nat Commun ; 12(1): 6061, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663818

RESUMO

Mutations in the epigenetic modifier TET2 are frequent in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS). Here, we investigate associations between TET2 mutations and DNA methylation in whole blood in 305 elderly twins, 15 patients with CCUS and 18 healthy controls. We find that TET2 mutations are associated with DNA hypermethylation at enhancer sites in whole blood in CHIP and in both granulocytes and mononuclear cells in CCUS. These hypermethylated sites are associated with leukocyte function and immune response and ETS-related and C/EBP-related transcription factor motifs. While the majority of TET2-associated hypermethylation sites are shared between CHIP and in AML, we find a set of AML-specific hypermethylated loci at active enhancer elements in hematopoietic stem cells. In summary, we show that TET2 mutations is associated with hypermethylated enhancers involved in myeloid differentiation in both CHIP, CCUS and AML patients.


Assuntos
Metilação de DNA , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Elementos Facilitadores Genéticos , Hematopoese/genética , Mutação , DNA (Citosina-5-)-Metiltransferases/genética , Células-Tronco Hematopoéticas , Humanos , Transtornos Mieloproliferativos/genética , Fatores de Transcrição/genética
4.
Molecules ; 26(20)2021 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-34684862

RESUMO

Iron fortifications are used for the treatment of iron-deficiency anemia; however, iron dosing may cause oxidative damage to the gut lumen. Thai Sinlek rice is abundant in iron and contains phytochemicals. We aimed at evaluating the effect of an iron-rice (IR) hydrolysate drink (100 mL/serving) on neurological function, red cell indices and iron status in elders. Healthy elderly subjects were divided into three non-anemic groups and one anemic group. The non-anemic groups consumed one WR (2 mg iron/serving) and two IR drinks (15 and 27 mg iron/serving) (groups A, B and D, respectively), while the anemic group consumed one IR drink (15 mg iron serving) (group C) every day for 30 days. There were no significant differences in the MMSE Thai 2002 and PHQ9 test scores for members of all groups, while the nutrition scores and body weight values of group D subjects were significantly increased. Hemoglobin (Hb) and mean corpuscular hemoglobin concentrations increased significantly only in group C. Serum iron and transferrin saturation levels tended to increase in group A, while these levels were decreased in members of group C. Serum antioxidant activity levels were increased in all groups, and were highest in group C. Thus, consumption of an IR drink for 15 days functioned to increase Hb and antioxidant capacity levels in anemic elders.


Assuntos
Anemia/dietoterapia , Índices de Eritrócitos , Compostos de Ferro/uso terapêutico , Oryza , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Antioxidantes , Bebidas , Encéfalo , Feminino , Hematopoese , Humanos , Ferro/sangue , Masculino , Valor Nutritivo , Oryza/química , Tailândia
5.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502137

RESUMO

In the bone marrow of vertebrates, two types of stem cells coexist-hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Hematopoiesis only occurs when these two stem cell types and their descendants interact. The descendants of HSCs supply the body with all the mature blood cells, while MSCs give rise to stromal cells that form a niche for HSCs and regulate the process of hematopoiesis. The studies of hematopoiesis were initially based on morphological observations, later extended by the use of physiological methods, and were subsequently augmented by massive application of sophisticated molecular techniques. The combination of these methods produced a wealth of new data on the organization and functional features of hematopoiesis in the ontogenesis of mammals and humans. This review summarizes the current views on hematopoiesis in mice and humans, discusses the development of blood elements and hematopoiesis in the embryo, and describes how the hematopoietic system works in the adult organism and how it changes during aging.


Assuntos
Envelhecimento/sangue , Hematopoese , Células-Tronco Hematopoéticas/citologia , Envelhecimento/metabolismo , Animais , Medula Óssea/crescimento & desenvolvimento , Humanos
6.
Nat Commun ; 12(1): 5528, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34545085

RESUMO

Inferring cellular trajectories using a variety of omic data is a critical task in single-cell data science. However, accurate prediction of cell fates, and thereby biologically meaningful discovery, is challenged by the sheer size of single-cell data, the diversity of omic data types, and the complexity of their topologies. We present VIA, a scalable trajectory inference algorithm that overcomes these limitations by using lazy-teleporting random walks to accurately reconstruct complex cellular trajectories beyond tree-like pathways (e.g., cyclic or disconnected structures). We show that VIA robustly and efficiently unravels the fine-grained sub-trajectories in a 1.3-million-cell transcriptomic mouse atlas without losing the global connectivity at such a high cell count. We further apply VIA to discovering elusive lineages and less populous cell fates missed by other methods across a variety of data types, including single-cell proteomic, epigenomic, multi-omics datasets, and a new in-house single-cell morphological dataset.


Assuntos
Algoritmos , Genômica , Análise de Célula Única , Animais , Ciclo Celular , Diferenciação Celular , Linhagem Celular Tumoral , Forma Celular , Hematopoese , Humanos , Ilhotas Pancreáticas/citologia , Proteínas com Homeodomínio LIM/metabolismo , Mesoderma/citologia , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Organogênese , Fatores de Transcrição/metabolismo
7.
Blood Adv ; 5(17): 3362-3372, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477819

RESUMO

The use of umbilical cord blood transplant has been substantially limited by the finite number of hematopoietic stem and progenitor cells in a single umbilical cord blood unit. Small molecules that not only quantitatively but also qualitatively stimulate enhancement of hematopoietic stem cell (HSC) self-renewal ex vivo should facilitate the clinical use of HSC transplantation and gene therapy. Recent evidence has suggested that the cyclin-dependent kinase inhibitor, p18INK4C (p18), is a critical regulator of mice HSC self-renewal. The role of p18 in human HSCs and the effect of p18 inhibitor on human HSC expansion ex vivo need further studies. Here we report that knockdown of p18 allowed for an increase in long-term colony-forming cells in vitro. We then identified an optimized small molecule inhibitor of p18, 005A, to induce ex vivo expansion of HSCs that was capable of reconstituting human hematopoiesis for at least 4 months in immunocompromised mice, and hence, similarly reconstituted secondary recipients for at least 4 more months, indicating that cells exposed to 005A were still competent in secondary recipients. Mechanistic studies showed that 005A might delay cell division and activate both the Notch signaling pathway and expression of transcription factor HoxB4, leading to enhancement of the self-renewal of long-term engrafting HSCs and the pool of progenitor cells. Taken together, these observations support a role for p18 in human HSC maintenance and that the p18 inhibitor 005A can enhance the self-renewal of long-term HSCs.


Assuntos
Inibidor de Quinase Dependente de Ciclina p18 , Células-Tronco Hematopoéticas , Animais , Benzoatos , Ciclo Celular , Inibidor de Quinase Dependente de Ciclina p18/genética , Hematopoese , Humanos , Camundongos
8.
Rinsho Ketsueki ; 62(8): 892-899, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497228

RESUMO

Clonal hematopoiesis (CH) harboring a leukemia-related mutation has been recently found in about 10% of healthy elderly individuals, which has been attracting attention. Although most people with CH do not develop hematological malignancies, some may develop hematological malignancies 10 times more frequently than age-matched controls. On the other hand, compared to age-matched controls, the probability of developing cardiovascular diseases in people with CH is 2-fold, which is thought to shorten the life expectancy. Moreover, one out of four patients with solid cancer and one out of two patients with aplastic anemia, whose mutation profiles overlap with but are distinct from common mutations identified with CH of elderly people, harbor CH. The study of CH has just begun, and there are many unknowns. In an aging society of unprecedented proportions, which is also attracting attention from the society, the establishment of a new research field that investigates CH in the near future is likely.


Assuntos
Anemia Aplástica , Neoplasias Hematológicas , Idoso , Envelhecimento , Anemia Aplástica/genética , Hematopoiese Clonal , Neoplasias Hematológicas/genética , Hematopoese/genética , Humanos , Mutação
9.
Cell Stem Cell ; 28(11): 1966-1981.e6, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34473945

RESUMO

DDX41 mutations are the most common germline alterations in adult myelodysplastic syndromes (MDSs). The majority of affected individuals harbor germline monoallelic frameshift DDX41 mutations and subsequently acquire somatic mutations in their other DDX41 allele, typically missense R525H. Hematopoietic progenitor cells (HPCs) with biallelic frameshift and R525H mutations undergo cell cycle arrest and apoptosis, causing bone marrow failure in mice. Mechanistically, DDX41 is essential for small nucleolar RNA (snoRNA) processing, ribosome assembly, and protein synthesis. Although monoallelic DDX41 mutations do not affect hematopoiesis in young mice, a subset of aged mice develops features of MDS. Biallelic mutations in DDX41 are observed at a low frequency in non-dominant hematopoietic stem cell clones in bone marrow (BM) from individuals with MDS. Mice chimeric for monoallelic DDX41 mutant BM cells and a minor population of biallelic mutant BM cells develop hematopoietic defects at a younger age, suggesting that biallelic DDX41 mutant cells are disease modifying in the context of monoallelic DDX41 mutant BM.


Assuntos
RNA Helicases DEAD-box , Síndromes Mielodisplásicas , Animais , RNA Helicases DEAD-box/genética , Células Germinativas , Hematopoese/genética , Camundongos , Mutação/genética , Síndromes Mielodisplásicas/genética
10.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575874

RESUMO

Intestinal injury caused by ionizing radiation (IR) is a main clinical issue for patients with cancer receiving abdominal or pelvic radiotherapy. Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that the pineal gland in the brain normally secretes. The study aimed to disclose the potential function of melatonin in intestinal injury induced by IR and its mechanism. Pretreatment with melatonin enhanced the 30-day survival rate of the irradiated mice and promoted the recovery of the intestinal epithelium and hematopoietic function following abdominal irradiation (ABI). Melatonin altered the gene profile of the small intestines from mice following ABI. The enriched biological process terms for melatonin treatment prior to radiation were mainly involved in the immune process. LPS/IL-1-mediated inhibition of RXR Function, TWEAK signaling, and Toll-like receptor signaling were the most activated canonical pathways targeted by melatonin. An upstream analysis network showed that Tripartite motif-containing 24 (TRIM24) was the most significantly inhibited and S100 calcium binding protein A9 (S100A9) activated. TRIM24 activated atherogenesis and cell viability in breast cancer cell lines and S100A9 inhibited the metabolism of amino acids. Melatonin has radioprotective effects on ABI-caused intestinal injury. The mechanisms behind the beneficial effects of melatonin were involved in activation of the immunity. It is necessary to conduct further experiments to explore the underlying mechanisms.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Transporte/genética , Intestinos/lesões , Melatonina/farmacologia , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Abdome/efeitos da radiação , Animais , Calgranulina B/metabolismo , Proteínas de Transporte/metabolismo , Sobrevivência Celular , Citocina TWEAK/metabolismo , Dano ao DNA/efeitos da radiação , Feminino , Raios gama/efeitos adversos , Hematopoese/efeitos da radiação , Humanos , Linfócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/metabolismo , Fenótipo , Lesões Experimentais por Radiação/tratamento farmacológico , Radiação Ionizante , Receptores X de Retinoides/metabolismo , Fatores de Transcrição/metabolismo , Irradiação Corporal Total
11.
Blood Adv ; 5(20): 4285-4290, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34496012

RESUMO

During aging, hematopoietic stem cell (HSC) function wanes with important biological and clinical implications for benign and malignant hematology, and other comorbidities, such as cardiovascular disease. However, the molecular mechanisms regulating HSC aging remain incompletely defined. GATA2 haploinsufficiency driven clinical syndromes initially result in primary immunodeficiencies and routinely evolve into hematologic malignancies on acquisition of further epigenetic mutations in both young and older patients. Using a conditional mouse model of Gata2 haploinsufficiency, we discover that during aging Gata2 promotes HSC proliferation, monocytosis, and loss of the common lymphoid progenitor. Aging of Gata2 haploinsufficient mice also offsets enhanced HSC apoptosis and decreased granulocyte-macrophage progenitor number normally observed in young Gata2 haploinsufficient mice. Transplantation of elderly Gata2 haploinsufficient HSCs impairs HSC function with evidence of myeloid bias. Our data demonstrate that Gata2 regulates HSC aging and suggest the mechanisms by which Gata2 mediated HSC aging has an impact on the evolution of malignancies in GATA2 haploinsufficiency syndromes.


Assuntos
Deficiência de GATA2 , Idoso , Envelhecimento/genética , Animais , Proliferação de Células , Fator de Transcrição GATA2/genética , Hematopoese , Células-Tronco Hematopoéticas , Humanos , Camundongos
12.
Blood Adv ; 5(20): 3960-3974, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34500457

RESUMO

Bone marrow (BM) is the primary site of hematopoiesis and is responsible for a lifelong supply of all blood cell lineages. The process of hematopoiesis follows key intrinsic programs that also integrate instructive signals from the BM niche. First identified as an erythropoietin-potentiating factor, the tissue inhibitor of metalloproteinase (TIMP) protein family has expanded to 4 members and has widely come to be viewed as a classical regulator of tissue homeostasis. By virtue of metalloprotease inhibition, TIMPs not only regulate extracellular matrix turnover but also control growth factor bioavailability. The 4 mammalian TIMPs possess overlapping enzyme-inhibition profiles and have never been studied for their cumulative role in hematopoiesis. Here, we show that TIMPs are critical for postnatal B lymphopoiesis in the BM. TIMP-deficient mice have defective B-cell development arising at the pro-B-cell stage. Expression analysis of TIMPless hematopoietic cell subsets pointed to an altered B-cell program in the Lineage-Sca-1+c-Kit+ (LSK) cell fraction. Serial and competitive BM transplants identified a defect in TIMP-deficient hematopoietic stem and progenitor cells for B lymphopoiesis. In parallel, reverse BM transplants uncovered the extrinsic role of stromal TIMPs in pro- and pre-B-cell development. TIMP deficiency disrupted CXCL12 localization to LepR+ cells, and increased soluble CXCL12 within the BM niche. It also compromised the number and morphology of LepR+ cells. These data provide new evidence that TIMPs control the cellular and biochemical makeup of the BM niche and influence the LSK transcriptional program required for optimal B lymphopoiesis.


Assuntos
Células da Medula Óssea , Medula Óssea , Animais , Linfócitos B , Hematopoese , Camundongos , Inibidores Teciduais de Metaloproteinases/genética
13.
Nature ; 598(7880): 327-331, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34588693

RESUMO

Haematopoiesis in the bone marrow (BM) maintains blood and immune cell production throughout postnatal life. Haematopoiesis first emerges in human BM at 11-12 weeks after conception1,2, yet almost nothing is known about how fetal BM (FBM) evolves to meet the highly specialized needs of the fetus and newborn. Here we detail the development of FBM, including stroma, using multi-omic assessment of mRNA and multiplexed protein epitope expression. We find that the full blood and immune cell repertoire is established in FBM in a short time window of 6-7 weeks early in the second trimester. FBM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell subsets emerging for the first time. The substantial expansion of B lymphocytes in FBM contrasts with fetal liver at the same gestational age. Haematopoietic progenitors from fetal liver, FBM and cord blood exhibit transcriptional and functional differences that contribute to tissue-specific identity and cellular diversification. Endothelial cell types form distinct vascular structures that we show are regionally compartmentalized within FBM. Finally, we reveal selective disruption of B lymphocyte, erythroid and myeloid development owing to a cell-intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in Down syndrome (trisomy 21).


Assuntos
Células da Medula Óssea/citologia , Medula Óssea , Síndrome de Down/sangue , Síndrome de Down/imunologia , Feto/citologia , Hematopoese , Sistema Imunitário/citologia , Linfócitos B/citologia , Células Dendríticas/citologia , Síndrome de Down/metabolismo , Síndrome de Down/patologia , Células Endoteliais/patologia , Eosinófilos/citologia , Células Eritroides/citologia , Granulócitos/citologia , Humanos , Imunidade , Células Mieloides/citologia , Células Estromais/citologia
14.
PLoS Biol ; 19(9): e3001394, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34550965

RESUMO

The ZEB2 transcription factor has been demonstrated to play important roles in hematopoiesis and leukemic transformation. ZEB1 is a close family member of ZEB2 but has remained more enigmatic concerning its roles in hematopoiesis. Here, we show using conditional loss-of-function approaches and bone marrow (BM) reconstitution experiments that ZEB1 plays a cell-autonomous role in hematopoietic lineage differentiation, particularly as a positive regulator of monocyte development in addition to its previously reported important role in T-cell differentiation. Analysis of existing single-cell (sc) RNA sequencing (RNA-seq) data of early hematopoiesis has revealed distinctive expression differences between Zeb1 and Zeb2 in hematopoietic stem and progenitor cell (HSPC) differentiation, with Zeb2 being more highly and broadly expressed than Zeb1 except at a key transition point (short-term HSC [ST-HSC]➔MPP1), whereby Zeb1 appears to be the dominantly expressed family member. Inducible genetic inactivation of both Zeb1 and Zeb2 using a tamoxifen-inducible Cre-mediated approach leads to acute BM failure at this transition point with increased long-term and short-term hematopoietic stem cell numbers and an accompanying decrease in all hematopoietic lineage differentiation. Bioinformatics analysis of RNA-seq data has revealed that ZEB2 acts predominantly as a transcriptional repressor involved in restraining mature hematopoietic lineage gene expression programs from being expressed too early in HSPCs. ZEB1 appears to fine-tune this repressive role during hematopoiesis to ensure hematopoietic lineage fidelity. Analysis of Rosa26 locus-based transgenic models has revealed that Zeb1 as well as Zeb2 cDNA-based overexpression within the hematopoietic system can drive extramedullary hematopoiesis/splenomegaly and enhance monocyte development. Finally, inactivation of Zeb2 alone or Zeb1/2 together was found to enhance survival in secondary MLL-AF9 acute myeloid leukemia (AML) models attesting to the oncogenic role of ZEB1/2 in AML.


Assuntos
Linhagem da Célula , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Células da Medula Óssea/patologia , Diferenciação Celular , Regulação Neoplásica da Expressão Gênica , Hematopoese , Células-Tronco Hematopoéticas/patologia , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Transgênicos , RNA-Seq , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
15.
Cells ; 10(9)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34571873

RESUMO

Maternal high-fat diet (HFD) modulates vascular remodeling in adult offspring. Here, we investigated the impact of maternal HFD on abdominal aortic aneurysm (AAA) development. Female wild-type mice were fed an HFD or normal diet (ND). AAA was induced in eight-week-old pups using calcium chloride. Male offspring of HFD-fed dams (O-HFD) showed a significant enlargement in AAA compared with the offspring of ND-fed dams (O-ND). Positive-staining cells for tartrate-resistant acid phosphate (TRAP) and matrix metalloproteinase (MMP) activity were significantly increased in O-HFD. The pharmacological inhibition of osteoclastogenesis abolished the exaggerated AAA development in O-HFD. The in vitro tumor necrosis factor-α-induced osteoclast-like differentiation of bone marrow-derived macrophages showed a higher number of TRAP-positive cells and osteoclast-specific gene expressions in O-HFD. Consistent with an increased expression of nuclear factor of activated T cells 1 (NFATc1) in O-HFD, the nuclear protein expression of interferon regulatory factor 8 (IRF8), a transcriptional repressor, were much lower, with significantly increased H3K27me3 marks at the promoter region. The enhancer of zeste homolog 2 inhibitor treatment restored IRF8 expression, resulting in no difference in NFATc1 and TRAP expressions between the two groups. Our findings demonstrate that maternal HFD augments AAA expansion, accompanied by exaggerated osteoclast-like macrophage accumulation, suggesting the possibility of macrophage skewing via epigenetic reprogramming.


Assuntos
Aneurisma da Aorta Abdominal/genética , Diferenciação Celular/genética , Epigênese Genética/genética , Fatores Reguladores de Interferon/genética , Macrófagos/patologia , Osteoclastos/patologia , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Aneurisma da Aorta Abdominal/patologia , Dieta Hiperlipídica/efeitos adversos , Feminino , Hematopoese/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteogênese/genética , Gravidez
16.
Best Pract Res Clin Endocrinol Metab ; 35(4): 101564, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34417114

RESUMO

PURPOSE: Here we review the current knowledge on bone marrow adipocytes (BMAds) as active contributors to the regulation of the hematopoietic niche, and as potentially pivotal players in the progression of hematological malignancies. We highlight the hierarchical and functional heterogeneity of the adipocyte lineage within the bone marrow, and how potentially different contexts dictate their interactions with hematopoietic populations. RECENT FINDINGS: Growing evidence associates the adipocyte lineage with important functions in hematopoietic regulation within the BM niche. Initially proposed to serve as negative regulators of the hematopoietic microenvironment, studies have also demonstrated that BMAds positively influence the survival and maintenance of hematopoietic stem cells (HSCs). These seemingly incongruous findings may at least be partially explained by stage-specificity across the adipocytic differentiation axis and by BMAds subtypes, suggesting that the heterogeneity of these populations allows for differential context-based interactions. One such distinction relies on the location of adipocytes. Constitutive bone marrow adipose tissue (cBMAT) historically associates to the "yellow" marrow containing so-called "stable" BMAs larger in size, less responsive to stimuli, and linked to HSC quiescence. On the other hand, regulated bone marrow adipose tissue (rBMAT)-associated adipocytes, also referred to as "labile" are smaller, more responsive to hematopoietic demand and strategically situated in hematopoietically active regions of the skeleton. Here we propose a model where the effect of distinct BM stromal cell populations (BMSC) in hematopoiesis is structured along the BMSC-BMAd differentiation axis, and where the effects on HSC maintenance versus hematopoietic proliferation are segregated. In doing so, it is possible to explain how recently identified, adipocyte-primed leptin receptor-expressing, CXCL12-high adventitial reticular cells (AdipoCARs) and marrow adipose lineage precursor cells (MALPs) best support active hematopoietic cell proliferation, while adipose progenitor cells (APCs) and maturing BMAd gradually lose the capacity to support active hematopoiesis, favoring HSC quiescence. Implicated soluble mediators include MCP-1, PAI-1, NRP1, possibly DPP4 and limiting availability of CXCL12 and SCF. How remodeling occurs within the BMSC-BMAd differentiation axis is yet to be elucidated and will likely unravel a three-way regulation of the hematopoietic, bone, and adipocytic compartments orchestrated by vascular elements. The interaction of malignant hematopoietic cells with BMAds is precisely contributing to unravel specific mechanisms of remodeling. SUMMARY: BMAds are important operative components of the hematopoietic microenvironment. Their heterogeneity directs their ability to exert a range of regulatory capacities in a manner dependent on their hierarchical, spatial, and biological context. This complexity highlights the importance of (i) developing experimental tools and nomenclature adapted to address stage-specificity and heterogeneity across the BMSC-BMAd differentiation axis when reporting effects in hematopoiesis, (ii) interpreting gene reporter studies within this framework, and (iii) quantifying changes in all three compartments (hematopoiesis, adiposity and bone) when addressing interdependency.


Assuntos
Células da Medula Óssea , Nicho de Células-Tronco , Adiposidade , Medula Óssea , Hematopoese , Humanos
17.
Cell Stem Cell ; 28(10): 1838-1850.e10, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34343492

RESUMO

It is critical to understand how human quiescent long-term hematopoietic stem cells (LT-HSCs) sense demand from daily and stress-mediated cues and then transition into bioenergetically active progeny to differentiate and meet these cellular needs. However, the demand-adapted regulatory circuits of these early steps of hematopoiesis are largely unknown. Here we show that lysosomes, sophisticated nutrient-sensing and signaling centers, are regulated dichotomously by transcription factor EB (TFEB) and MYC to balance catabolic and anabolic processes required for activating LT-HSCs and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway causes membrane receptor degradation, limiting LT-HSC metabolic and mitogenic activation, promoting quiescence and self-renewal, and governing erythroid-myeloid commitment. In contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism, driving LT-HSC activation. Our study identifies TFEB-mediated control of lysosomal activity as a central regulatory hub for proper and coordinated stem cell fate determination.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Hematopoese , Células-Tronco Hematopoéticas , Diferenciação Celular , Células-Tronco Hematopoéticas/citologia , Humanos , Lisossomos , Transdução de Sinais
18.
Elife ; 102021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34463253

RESUMO

The bone marrow niche plays critical roles in hematopoietic recovery and hematopoietic stem cell (HSC) regeneration after myeloablative stress. However, it is not clear whether systemic factors beyond the local niche are required for these essential processes in vivo. Thrombopoietin (THPO) is a key cytokine promoting hematopoietic rebound after myeloablation and its transcripts are expressed by multiple cellular sources. The upregulation of bone marrow-derived THPO has been proposed to be crucial for hematopoietic recovery and HSC regeneration after stress. Nonetheless, the cellular source of THPO in myeloablative stress has never been investigated genetically. We assessed the functional sources of THPO following two common myeloablative perturbations: 5-fluorouracil (5-FU) administration and irradiation. Using a Thpo translational reporter, we found that the liver but not the bone marrow is the major source of THPO protein after myeloablation. Mice with conditional Thpo deletion from osteoblasts and/or bone marrow stromal cells showed normal recovery of HSCs and hematopoiesis after myeloablation. In contrast, mice with conditional Thpo deletion from hepatocytes showed significant defects in HSC regeneration and hematopoietic rebound after myeloablation. Thus, systemic THPO from the liver is necessary for HSC regeneration and hematopoietic recovery in myeloablative stress conditions.


Assuntos
Fluoruracila/farmacologia , Hematopoese/efeitos dos fármacos , Hematopoese/efeitos da radiação , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos da radiação , Hepatócitos/metabolismo , Agonistas Mieloablativos/farmacologia , Comunicação Parácrina , Trombopoetina/metabolismo , Animais , Células-Tronco Hematopoéticas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nicho de Células-Tronco/efeitos dos fármacos , Nicho de Células-Tronco/efeitos da radiação , Trombopoetina/genética , Fatores de Tempo
19.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445246

RESUMO

The hematopoietic system relies on regulation of both metabolism and autophagy to maintain its homeostasis, ensuring the self-renewal and multipotent differentiation potential of hematopoietic stem cells (HSCs). HSCs display a distinct metabolic profile from that of their differentiated progeny, while metabolic rewiring from glycolysis to oxidative phosphorylation (OXPHOS) has been shown to be crucial for effective hematopoietic differentiation. Autophagy-mediated regulation of metabolism modulates the distinct characteristics of quiescent and differentiating hematopoietic cells. In particular, mitophagy determines the cellular mitochondrial content, thus modifying the level of OXPHOS at the different differentiation stages of hematopoietic cells, while, at the same time, it ensures the building blocks and energy for differentiation. Aberrations in both the metabolic status and regulation of the autophagic machinery are implicated in the development of hematologic malignancies, especially in leukemogenesis. In this review, we aim to investigate the role of metabolism and autophagy, as well as their interconnections, in normal and malignant hematopoiesis.


Assuntos
Carcinogênese/metabolismo , Neoplasias Hematológicas/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Leucemia/metabolismo , Mitocôndrias/metabolismo , Mitofagia , Animais , Carcinogênese/patologia , Diferenciação Celular , Neoplasias Hematológicas/patologia , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia/patologia , Mitocôndrias/patologia
20.
Curr Opin Hematol ; 28(5): 308-314, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34397590

RESUMO

PURPOSE OF REVIEW: Megakaryocytes are rare hematopoietic cells that play an instrumental role in hemostasis, and other important biological processes such as immunity and wound healing. With the advent of cell reprogramming technologies and advances in differentiation protocols, it is now possible to obtain megakaryocytes from any pluripotent stem cell (PSC) via hematopoietic induction. Here, we review recent advances in PSC-derived megakaryocyte (iMK) technology, focusing on platform validation, disease modeling and current limitations. RECENT FINDINGS: A comprehensive study confirmed that iMK can recapitulate many transcriptional and functional aspects of megakaryocyte and platelet biology, including variables associated with complex genetic traits such as sex and race. These findings were corroborated by several pathological models in which iMKs revealed molecular mechanisms behind inherited platelet disorders and assessed the efficacy of novel pharmacological interventions. However, current differentiation protocols generate primarily embryonic iMK, limiting the clinical and translational potential of this system. SUMMARY: iMK are strong candidates to model pathologic mutations involved in platelet defects and develop innovative therapeutic strategies. Future efforts on generating definitive hematopoietic progenitors would improve current platelet generation protocols and expand our capacity to model neonatal and adult megakaryocyte disorders.


Assuntos
Transtornos Plaquetários , Diferenciação Celular , Doenças Genéticas Inatas , Hematopoese , Modelos Genéticos , Células-Tronco Pluripotentes/metabolismo , Animais , Transtornos Plaquetários/genética , Transtornos Plaquetários/metabolismo , Transtornos Plaquetários/terapia , Plaquetas/metabolismo , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/terapia , Humanos , Megacariócitos/metabolismo
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