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1.
EMBO J ; 41(8): e110942, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35274751

RESUMO

How blood stem cells balance fate decisions between quiescence maintenance and differentiation during recovery from cancer treatment remains poorly understood. A recent study by Umemoto et al (2022) uncovers an unexpected linkage between metabolic and epigenetic regulation of haematopoiesis, suggesting new targets in haematopoietic regeneration, with possible implications in leukaemogenesis and therapy resistance.


Assuntos
Epigênese Genética , Células-Tronco Hematopoéticas , Carcinogênese/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/fisiologia , Humanos
2.
Circ Res ; 127(11): e252-e270, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-32921258

RESUMO

RATIONALE: The molecular mechanisms underlying the formation of coronary arteries during development and during cardiac neovascularization after injury are poorly understood. However, a detailed description of the relevant signaling pathways and functional TFs (transcription factors) regulating these processes is still incomplete. OBJECTIVE: The goal of this study is to identify novel cardiac transcriptional mechanisms of coronary angiogenesis and vessel remodeling by defining the molecular signatures of coronary vascular endothelial cells during these complex processes. METHODS AND RESULTS: We demonstrate that Nes-gfp and Nes-CreERT2 transgenic mouse lines are novel tools for studying the emergence of coronary endothelium and targeting sprouting coronary vessels (but not ventricular endocardium) during development. Furthermore, we identify Sox17 as a critical TF upregulated during the sprouting and remodeling of coronary vessels, visualized by a specific neural enhancer from the Nestin gene that is strongly induced in developing arterioles. Functionally, genetic-inducible endothelial deletion of Sox17 causes deficient cardiac remodeling of coronary vessels, resulting in improper coronary artery formation. CONCLUSIONS: We demonstrated that Sox17 TF regulates the transcriptional activation of Nestin's enhancer in developing coronary vessels while its genetic deletion leads to inadequate coronary artery formation. These findings identify Sox17 as a critical regulator for the remodeling of coronary vessels in the developing heart.


Assuntos
Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Proteínas HMGB/metabolismo , Neovascularização Fisiológica , Nestina/metabolismo , Fatores de Transcrição SOXF/metabolismo , Remodelação Vascular , Animais , Linhagem da Célula , Células Cultivadas , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Vasos Coronários/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas HMGB/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfogênese , Nestina/genética , Fatores de Transcrição SOXF/genética , Transcrição Gênica , Ativação Transcricional , Transcriptoma
3.
Blood ; 133(3): 224-236, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30361261

RESUMO

Hematopoietic stem and progenitor cells (HSPCs) and leukocytes circulate between the bone marrow (BM) and peripheral blood following circadian oscillations. Autonomic sympathetic noradrenergic signals have been shown to regulate HSPC and leukocyte trafficking, but the role of the cholinergic branch has remained unexplored. We have investigated the role of the cholinergic nervous system in the regulation of day/night traffic of HSPCs and leukocytes in mice. We show here that the autonomic cholinergic nervous system (including parasympathetic and sympathetic) dually regulates daily migration of HSPCs and leukocytes. At night, central parasympathetic cholinergic signals dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes. However, during the daytime, derepressed sympathetic noradrenergic activity causes predominant BM egress of HSPCs and leukocytes via ß3-adrenergic receptor. This egress is locally supported by light-triggered sympathetic cholinergic activity, which inhibits BM vascular cell adhesion and homing. In summary, central (parasympathetic) and local (sympathetic) cholinergic signals regulate day/night oscillations of circulating HSPCs and leukocytes. This study shows how both branches of the autonomic nervous system cooperate to orchestrate daily traffic of HSPCs and leukocytes.


Assuntos
Movimento Celular , Colinérgicos/farmacologia , Ritmo Circadiano , Células-Tronco Hematopoéticas/fisiologia , Leucócitos/fisiologia , Sistema Nervoso Parassimpático/fisiologia , Sistema Nervoso Simpático/fisiologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/fisiologia , Adesão Celular , Células Cultivadas , Quimiotaxia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Feminino , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Adrenérgicos beta 2 , Receptores Adrenérgicos beta 3/fisiologia , Receptores Acoplados a Proteínas G/fisiologia
4.
Ann Rheum Dis ; 79(12): 1625-1634, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32963046

RESUMO

OBJECTIVES: Osteophytes are highly prevalent in osteoarthritis (OA) and are associated with pain and functional disability. These pathological outgrowths of cartilage and bone typically form at the junction of articular cartilage, periosteum and synovium. The aim of this study was to identify the cells forming osteophytes in OA. METHODS: Fluorescent genetic cell-labelling and tracing mouse models were induced with tamoxifen to switch on reporter expression, as appropriate, followed by surgery to induce destabilisation of the medial meniscus. Contributions of fluorescently labelled cells to osteophytes after 2 or 8 weeks, and their molecular identity, were analysed by histology, immunofluorescence staining and RNA in situ hybridisation. Pdgfrα-H2BGFP mice and Pdgfrα-CreER mice crossed with multicolour Confetti reporter mice were used for identification and clonal tracing of mesenchymal progenitors. Mice carrying Col2-CreER, Nes-CreER, LepR-Cre, Grem1-CreER, Gdf5-Cre, Sox9-CreER or Prg4-CreER were crossed with tdTomato reporter mice to lineage-trace chondrocytes and stem/progenitor cell subpopulations. RESULTS: Articular chondrocytes, or skeletal stem cells identified by Nes, LepR or Grem1 expression, did not give rise to osteophytes. Instead, osteophytes derived from Pdgfrα-expressing stem/progenitor cells in periosteum and synovium that are descendants from the Gdf5-expressing embryonic joint interzone. Further, we show that Sox9-expressing progenitors in periosteum supplied hybrid skeletal cells to the early osteophyte, while Prg4-expressing progenitors from synovial lining contributed to cartilage capping the osteophyte, but not to bone. CONCLUSION: Our findings reveal distinct periosteal and synovial skeletal progenitors that cooperate to form osteophytes in OA. These cell populations could be targeted in disease modification for treatment of OA.


Assuntos
Osteoartrite/patologia , Osteófito/patologia , Periósteo/patologia , Células-Tronco/patologia , Membrana Sinovial/patologia , Animais , Linhagem da Célula , Camundongos
5.
Haematologica ; 105(1): 38-46, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31806690

RESUMO

Hematopoietic stem cell (HSC) aging was originally thought to be essentially an HSC-autonomous process, which is the focus of another review in the same issue of Haematologica However, studies on the microenvironment that maintains and regulates HSC (HSC niche) over the past 20 years have suggested that microenvironmental aging contributes to declined HSC function over time. The HSC niches comprise a complex and dynamic molecular network of interactions across multiple cell types, including endothelial cells, mesenchymal stromal cells, osteoblasts, adipocytes, neuroglial cells and mature hematopoietic cells. Upon aging, functional changes in the HSC niches, such as microenvironmental senescence, imbalanced bone marrow mesenchymal stromal cell differentiation, vascular remodeling, changes in adrenergic signaling and inflammation, coordinately and dynamically influence the fate of HSC and their downstream progeny. The end result is lymphoid deficiency and myeloid skewing. During this process, aged HSC and their derivatives remodel the niche to favor myeloid expansion. Therefore, the crosstalk between HSC and the microenvironment is indispensable for the aging of the hematopoietic system and might represent a therapeutic target in age-related pathological disorders.


Assuntos
Células Endoteliais , Células-Tronco Hematopoéticas , Diferenciação Celular , Nicho de Células-Tronco
6.
Immunity ; 34(4): 590-601, 2011 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-21458307

RESUMO

Inflammatory (Ly6C(hi) CCR2+) monocytes provide defense against infections but also contribute to autoimmune diseases and atherosclerosis. Monocytes originate from bone marrow and their entry into the bloodstream requires stimulation of CCR2 chemokine receptor by monocyte chemotactic protein-1 (MCP1). How monocyte emigration from bone marrow is triggered by remote infections remains unclear. We demonstrated that low concentrations of Toll-like receptor (TLR) ligands in the bloodstream drive CCR2-dependent emigration of monocytes from bone marrow. Bone marrow mesenchymal stem cells (MSCs) and their progeny, including CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells, rapidly expressed MCP1 in response to circulating TLR ligands or bacterial infection and induced monocyte trafficking into the bloodstream. Targeted deletion of MCP1 from MSCs impaired monocyte emigration from bone marrow. Our findings suggest that bone marrow MSCs and CAR cells respond to circulating microbial molecules and regulate bloodstream monocyte frequencies by secreting MCP1 in proximity to bone marrow vascular sinuses.


Assuntos
Medula Óssea/imunologia , Movimento Celular , Células-Tronco Mesenquimais/imunologia , Monócitos/citologia , Monócitos/imunologia , Receptores Toll-Like/imunologia , Animais , Ligantes , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores CCR2/imunologia
7.
Nature ; 512(7512): 78-81, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-25043017

RESUMO

Myeloproliferative neoplasms (MPNs) are diseases caused by mutations in the haematopoietic stem cell (HSC) compartment. Most MPN patients have a common acquired mutation of Janus kinase 2 (JAK2) gene in HSCs that renders this kinase constitutively active, leading to uncontrolled cell expansion. The bone marrow microenvironment might contribute to the clinical outcomes of this common event. We previously showed that bone marrow nestin(+) mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibres regulate normal HSCs. Here we demonstrate that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibres, supporting Schwann cells and nestin(+) MSCs are consistently reduced in the bone marrow of MPN patients and mice expressing the human JAK2(V617F) mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by bone marrow neural damage and Schwann cell death triggered by interleukin-1ß produced by mutant HSCs. In turn, in vivo depletion of nestin(+) cells or their production of CXCL12 expanded mutant HSC number and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with ß3-adrenergic agonists that restored the sympathetic regulation of nestin(+) MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing the number of leukaemic stem cells. Our results demonstrate that mutant-HSC-driven niche damage critically contributes to disease manifestation in MPN and identify niche-forming MSCs and their neural regulation as promising therapeutic targets.


Assuntos
Células-Tronco Hematopoéticas/patologia , Transtornos Mieloproliferativos/patologia , Neoplasias/patologia , Fibras Nervosas/patologia , Nicho de Células-Tronco , Sistema Nervoso Simpático/patologia , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Progressão da Doença , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Interleucina-1beta/metabolismo , Janus Quinase 2/genética , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/patologia , Camundongos , Transtornos Mieloproliferativos/tratamento farmacológico , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Fibras Nervosas/efeitos dos fármacos , Nestina/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Receptores Adrenérgicos beta 3/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/patologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia
9.
Blood ; 129(7): 811-822, 2017 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-28064238

RESUMO

Research in the last few years has revealed a sophisticated interaction network between multiple bone marrow cells that regulate different hematopoietic stem cell (HSC) properties such as proliferation, differentiation, localization, and self-renewal during homeostasis. These mechanisms are essential to keep the physiological HSC numbers in check and interfere with malignant progression. In addition to the identification of multiple mutations and chromosomal aberrations driving the progression of myeloid malignancies, alterations in the niche compartment recently gained attention for contributing to disease progression. Leukemic cells can remodel the niche into a permissive environment favoring leukemic stem cell expansion over normal HSC maintenance, and evidence is accumulating that certain niche alterations can even induce leukemic transformation. Relapse after chemotherapy is still a major challenge during treatment of myeloid malignancies, and cure is only rarely achieved. Recent progress in understanding the niche-imposed chemoresistance mechanisms will likely contribute to the improvement of current therapeutic strategies. This article discusses the role of different niche cells and their stage- and disease-specific roles during progression of myeloid malignancies and in response to chemotherapy.


Assuntos
Células-Tronco Hematopoéticas/patologia , Leucemia Mieloide/patologia , Células Mieloides/patologia , Células-Tronco Neoplásicas/patologia , Antineoplásicos/uso terapêutico , Medula Óssea/irrigação sanguínea , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Leucemia Mieloide/tratamento farmacológico , Células Mieloides/efeitos dos fármacos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Nicho de Células-Tronco/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
10.
Haematologica ; 104(10): 1928-1934, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31515356

RESUMO

In this review article, we present recent updates on the hematologic tumor microenvironment following the 3rd Scientific Workshop on the Haematological Tumour Microenvironment and its Therapeutic Targeting organized by the European School of Hematology, which took place at the Francis Crick Institute in London in February 2019. This review article is focused on recent scientific advances highlighted in the invited presentations at the meeting, which encompassed the normal and malignant niches supporting hematopoietic stem cells and their progeny. Given the precise focus, it does not discuss other relevant contributions in this field, which have been the scope of other recent reviews. The content covers basic research and possible clinical applications with the major therapeutic angle of utilizing basic knowledge to devise new strategies to target the tumor microenvironment in hematologic cancers. The review is structured in the following sections: (i) regulation of normal hematopoietic stem cell niches during development, adulthood and aging; (ii) metabolic adaptation and reprogramming in the tumor microenvironment; (iii) the key role of inflammation in reshaping the normal microenvironment and driving hematopoietic stem cell proliferation; (iv) current understanding of the tumor microenvironment in different malignancies, such as chronic lymphocytic leukemia, multiple myeloma, acute myeloid leukemia and myelodysplastic syndromes; and (v) the effects of therapies on the microenvironment and some opportunities to target the niche directly in order to improve current treatments.


Assuntos
Neoplasias Hematológicas/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Microambiente Tumoral , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Células-Tronco Hematopoéticas/patologia , Humanos
11.
Haematologica ; 104(4): 710-716, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30409796

RESUMO

The ß-3 sympathomimetic agonist BRL37344 restored nestin-positive cells within the stem cell niche, and thereby normalized blood counts and improved myelofibrosis in a mouse model of JAK2-V617F-positive myeloproliferative neoplasms. We therefore tested the effectiveness of mirabegron, a ß-3 sympathomimetic agonist, in a phase II trial including 39 JAK2-V617F-positive patients with myeloproliferative neoplasms and a mutant allele burden more than 20%. Treatment consisted of mirabegron 50 mg daily for 24 weeks. The primary end point was reduction of JAK2-V617F allele burden of 50% or over, but this was not reached in any of the patients. One patient achieved a 25% reduction in JAK2-V617F allele burden by 24 weeks. A small subgroup of patients showed hematologic improvement. As a side study, bone marrow biopsies were evaluated in 20 patients. We found an increase in the nestin+ cells from a median of 1.09 (interquartile range 0.38-3.27)/mm2 to 3.95 (interquartile range 1.98-8.79)/mm2 (P<0.0001) and a slight decrease of reticulin fibrosis from a median grade of 1.0 (interquartile range 0-3) to 0.5 (interquartile range 0-2) (P=0.01) between start and end of mirabegron treatment. Despite the fact that the primary end point of reducing JAK2-V617F allele burden was not reached, the observed effects on nestin+ mesenchymal stem cells and reticulin fibrosis is encouraging, and shows that mirabegron can modify the microenvironment where the JAK2-mutant stem cells are maintained. (Registered at clinicaltrials.gov identifier: 02311569).


Assuntos
Acetanilidas/administração & dosagem , Neoplasias Hematológicas , Janus Quinase 2 , Mutação de Sentido Incorreto , Transtornos Mieloproliferativos , Nestina , Reticulina , Simpatomiméticos/administração & dosagem , Tiazóis/administração & dosagem , Acetanilidas/efeitos adversos , Adulto , Substituição de Aminoácidos , Animais , Feminino , Fibrose , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Nestina/genética , Nestina/metabolismo , Reticulina/genética , Reticulina/metabolismo , Simpatomiméticos/efeitos adversos , Tiazóis/efeitos adversos
12.
Cell Mol Life Sci ; 74(4): 579-590, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27436341

RESUMO

Research in the last decade has shown that hematopoietic stem cells (HSCs) interact with and are modulated by a complex multicellular microenvironment in the bone marrow, which includes both the HSC progeny and multiple non-hematopoietic cell types. Intense work is gradually throwing light on the composition of the HSC niche and the molecular cues exchanged between its components, which has implications for HSC production, maintenance and expansion. In addition, it has become apparent that bidirectional interactions between leukemic cells and their niche play a previously unrecognized role in the initiation and development of hematological malignancies. Consequently, targeting of the malignant niche holds considerable promise for more specific antileukemic therapies. Here we summarize the latest insights into HSC niche biology and recent work showing multiple connections between hematological malignancy and alterations in the bone marrow microenvironment.


Assuntos
Medula Óssea/patologia , Células-Tronco Hematopoéticas/patologia , Leucemia/patologia , Células-Tronco Neoplásicas/patologia , Nicho de Células-Tronco , Microambiente Tumoral , Animais , Neoplasias Hematológicas/patologia , Células-Tronco Hematopoéticas/citologia , Humanos , Células-Tronco Neoplásicas/citologia
13.
Mol Cell Proteomics ; 15(5): 1740-60, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26893027

RESUMO

The coordinated behavior of proteins is central to systems biology. However, the underlying mechanisms are poorly known and methods to analyze coordination by conventional quantitative proteomics are still lacking. We present the Systems Biology Triangle (SBT), a new algorithm that allows the study of protein coordination by pairwise quantitative proteomics. The Systems Biology Triangle detected statistically significant coordination in diverse biological models of very different nature and subjected to different kinds of perturbations. The Systems Biology Triangle also revealed with unprecedented molecular detail an array of coordinated, early protein responses in vascular smooth muscle cells treated at different times with angiotensin-II. These responses included activation of protein synthesis, folding, turnover, and muscle contraction - consistent with a differentiated phenotype-as well as the induction of migration and the repression of cell proliferation and secretion. Remarkably, the majority of the altered functional categories were protein complexes, interaction networks, or metabolic pathways. These changes could not be detected by other algorithms widely used by the proteomics community, and the vast majority of proteins involved have not been described before to be regulated by AngII. The unique capabilities of The Systems Biology Triangle to detect functional protein alterations produced by the coordinated action of proteins in pairwise quantitative proteomics experiments make this algorithm an attractive choice for the biological interpretation of results on a routine basis.


Assuntos
Proteoma/análise , Proteômica/métodos , Biologia de Sistemas/métodos , Algoritmos , Animais , Ensaios de Triagem em Larga Escala , Humanos , Mapas de Interação de Proteínas
15.
Blood ; 134(15): 1197-1198, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31698415
16.
Blood ; 124(19): 2937-47, 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25202142

RESUMO

The glycosyltransferase gene, Ext1, is essential for heparan sulfate production. Induced deletion of Ext1 selectively in Mx1-expressing bone marrow (BM) stromal cells, a known population of skeletal stem/progenitor cells, in adult mice resulted in marked changes in hematopoietic stem and progenitor cell (HSPC) localization. HSPC egressed from BM to spleen after Ext1 deletion. This was associated with altered signaling in the stromal cells and with reduced vascular cell adhesion molecule 1 production by them. Further, pharmacologic inhibition of heparan sulfate mobilized qualitatively more potent and quantitatively more HSPC from the BM than granulocyte colony-stimulating factor alone, including in a setting of granulocyte colony-stimulating factor resistance. The reduced presence of endogenous HSPC after Ext1 deletion was associated with engraftment of transfused HSPC without any toxic conditioning of the host. Therefore, inhibiting heparan sulfate production may provide a means for avoiding the toxicities of radiation or chemotherapy in HSPC transplantation for nonmalignant conditions.


Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Heparitina Sulfato/biossíntese , N-Acetilglucosaminiltransferases/metabolismo , Células Estromais/metabolismo , Condicionamento Pré-Transplante , Animais , Anticoagulantes/farmacologia , Ligação Competitiva/imunologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/metabolismo , Fator Estimulador de Colônias de Granulócitos/farmacologia , Proteínas de Fluorescência Verde/genética , Heparina/farmacologia , Heparitina Sulfato/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , N-Acetilglucosaminiltransferases/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células Estromais/imunologia , Molécula 1 de Adesão de Célula Vascular/imunologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
17.
Nature ; 466(7308): 829-34, 2010 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-20703299

RESUMO

The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.


Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Mesenquimais/citologia , Nicho de Células-Tronco/citologia , Animais , Diferenciação Celular/efeitos dos fármacos , Divisão Celular , Linhagem da Célula/efeitos dos fármacos , Movimento Celular , Células Cultivadas , Quimiocina CXCL12/metabolismo , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Fator Estimulador de Colônias de Granulócitos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Transgênicos , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/efeitos dos fármacos , Células-Tronco Multipotentes/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nestina , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Hormônio Paratireóideo/farmacologia , Nicho de Células-Tronco/efeitos dos fármacos , Nicho de Células-Tronco/metabolismo , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Sistema Nervoso Simpático/fisiologia
18.
Blood ; 130(18): 1960-1961, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-29097370
19.
Blood ; 119(17): 3962-5, 2012 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-22422821

RESUMO

The mechanisms mediating hematopoietic stem and progenitor cell (HSPC) mobilization by G-CSF are complex. We have found previously that G-CSF-enforced mobilization is controlled by peripheral sympathetic nerves via norepinephrine (NE) signaling. In the present study, we show that G-CSF likely alters sympathetic tone directly and that methods to increase adrenergic activity in the BM microenvironment enhance progenitor mobilization. Peripheral sympathetic nerve neurons express the G-CSF receptor and ex vivo stimulation of peripheral sympathetic nerve neurons with G-CSF reduced NE reuptake significantly, suggesting that G-CSF potentiates the sympathetic tone by increasing NE availability. Based on these data, we investigated the NE reuptake inhibitor desipramine in HSPC mobilization. Whereas desipramine did not by itself elicit circulating HSPCs, it increased G-CSF-triggered mobilization efficiency significantly and rescued mobilization in a model mimicking "poor mobilizers." Therefore, these data suggest that blockade of NE reuptake may be a novel therapeutic target to increase stem cell yield in patients.


Assuntos
Movimento Celular/fisiologia , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Norepinefrina/metabolismo , Animais , Células Cultivadas , Imunofluorescência , Fator Estimulador de Colônias de Granulócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Nervoso Simpático/citologia , Sistema Nervoso Simpático/metabolismo
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