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1.
Annu Rev Immunol ; 35: 119-147, 2017 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-28125357

RESUMO

The intestinal epithelial barrier includes columnar epithelial, Paneth, goblet, enteroendocrine, and tuft cells as well as other cell populations, all of which contribute properties essential for gastrointestinal homeostasis. The intestinal mucosa is covered by mucin, which contains antimicrobial peptides and secretory IgA and prevents luminal bacteria, fungi, and viruses from stimulating intestinal immune responses. Conversely, the transport of luminal microorganisms-mediated by M, dendritic, and goblet cells-into intestinal tissues facilitates the harmonization of active and quiescent mucosal immune responses. The bacterial population within gut-associated lymphoid tissues creates the intratissue cohabitations for harmonized mucosal immunity. Intermolecular and intercellular communication among epithelial, immune, and mesenchymal cells creates an environment conducive for epithelial regeneration and mucosal healing. This review summarizes the so-called intestinal mucosal ecological network-the complex but vital molecular and cellular interactions of epithelial mesenchymal cells, immune cells, and commensal microbiota that achieve intestinal homeostasis, regeneration, and healing.


Assuntos
Células Epiteliais/fisiologia , Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/imunologia , Animais , Comunicação Celular , Homeostase , Humanos , Imunidade Inata , Imunoglobulina A/metabolismo , Mucosa Intestinal/patologia , Cicatrização
2.
Cell ; 187(12): 3120-3140.e29, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38714197

RESUMO

Non-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely uncharacterized. We used single-cell RNA sequencing (scRNA-seq) to profile 29,325 non-hematopoietic cells and discovered nine transcriptionally distinct subtypes. We simultaneously profiled 53,417 hematopoietic cells and predicted their interactions with non-hematopoietic subsets. We employed co-detection by indexing (CODEX) to spatially profile over 1.2 million cells. We integrated scRNA-seq and CODEX data to link predicted cellular signaling with spatial proximity. Our analysis revealed a hyperoxygenated arterio-endosteal neighborhood for early myelopoiesis, and an adipocytic localization for early hematopoietic stem and progenitor cells (HSPCs). We used our CODEX atlas to annotate new images and uncovered mesenchymal stromal cell (MSC) expansion and spatial neighborhoods co-enriched for leukemic blasts and MSCs in acute myeloid leukemia (AML) patient samples. This spatially resolved, multiomic atlas of human bone marrow provides a reference for investigation of cellular interactions that drive hematopoiesis.


Assuntos
Medula Óssea , Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Proteômica , Análise de Célula Única , Transcriptoma , Humanos , Análise de Célula Única/métodos , Medula Óssea/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Proteômica/métodos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Hematopoese , Nicho de Células-Tronco , Células da Medula Óssea/metabolismo , Células da Medula Óssea/citologia
3.
Cell ; 187(11): 2801-2816.e17, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38657601

RESUMO

The niche is typically considered as a pre-established structure sustaining stem cells. Therefore, the regulation of its formation remains largely unexplored. Whether distinct molecular mechanisms control the establishment versus maintenance of a stem cell niche is unknown. To address this, we compared perinatal and adult bone marrow mesenchymal stromal cells (MSCs), a key component of the hematopoietic stem cell (HSC) niche. MSCs exhibited enrichment in genes mediating m6A mRNA methylation at the perinatal stage and downregulated the expression of Mettl3, the m6A methyltransferase, shortly after birth. Deletion of Mettl3 from developing MSCs but not osteoblasts led to excessive osteogenic differentiation and a severe HSC niche formation defect, which was significantly rescued by deletion of Klf2, an m6A target. In contrast, deletion of Mettl3 from MSCs postnatally did not affect HSC niche. Stem cell niche generation and maintenance thus depend on divergent molecular mechanisms, which may be exploited for regenerative medicine.


Assuntos
Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Metiltransferases , Camundongos Endogâmicos C57BL , Nicho de Células-Tronco , Animais , Camundongos , Adenosina/metabolismo , Adenosina/análogos & derivados , Diferenciação Celular , Epigênese Genética , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Fatores de Transcrição Kruppel-Like , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Metiltransferases/metabolismo , Metiltransferases/genética , Osteoblastos/metabolismo , Osteoblastos/citologia , Osteogênese , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Transcriptoma/genética , Humanos
4.
Cell ; 184(1): 243-256.e18, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33417861

RESUMO

Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering development of urgently needed innovative therapies. Here, we show that Twist1+/- mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure, and rescues neurocognitive behavior deficits. The regenerated suture creates a niche into which endogenous MSCs migrated, sustaining calvarial bone homeostasis and repair. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease.


Assuntos
Cognição/fisiologia , Suturas Cranianas/fisiopatologia , Craniossinostoses/fisiopatologia , Regeneração/fisiologia , Crânio/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Craniossinostoses/genética , Dura-Máter/patologia , Dura-Máter/fisiopatologia , Gelatina/farmacologia , Perfilação da Expressão Gênica , Força da Mão , Pressão Intracraniana/efeitos dos fármacos , Pressão Intracraniana/fisiologia , Locomoção/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Metacrilatos/farmacologia , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Crânio/patologia , Proteína 1 Relacionada a Twist/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
5.
Cell ; 184(14): 3774-3793.e25, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34115982

RESUMO

Cytomegaloviruses (CMVs) have co-evolved with their mammalian hosts for millions of years, leading to remarkable host specificity and high infection prevalence. Macrophages, which already populate barrier tissues in the embryo, are the predominant immune cells at potential CMV entry sites. Here we show that, upon CMV infection, macrophages undergo a morphological, immunophenotypic, and metabolic transformation process with features of stemness, altered migration, enhanced invasiveness, and provision of the cell cycle machinery for viral proliferation. This complex process depends on Wnt signaling and the transcription factor ZEB1. In pulmonary infection, mouse CMV primarily targets and reprograms alveolar macrophages, which alters lung physiology and facilitates primary CMV and secondary bacterial infection by attenuating the inflammatory response. Thus, CMV profoundly perturbs macrophage identity beyond established limits of plasticity and rewires specific differentiation processes, allowing viral spread and impairing innate tissue immunity.


Assuntos
Citomegalovirus/fisiologia , Macrófagos Alveolares/virologia , Animais , Apresentação de Antígeno , Efeito Espectador , Ciclo Celular , Linhagem Celular Transformada , Reprogramação Celular , Citomegalovirus/patogenicidade , Citomegalovirus/ultraestrutura , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Proteínas de Fluorescência Verde/metabolismo , Pulmão/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/ultraestrutura , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fenótipo , Células-Tronco/patologia , Replicação Viral/fisiologia , Via de Sinalização Wnt
6.
Cell ; 184(3): 810-826.e23, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33406409

RESUMO

Development of the human intestine is not well understood. Here, we link single-cell RNA sequencing and spatial transcriptomics to characterize intestinal morphogenesis through time. We identify 101 cell states including epithelial and mesenchymal progenitor populations and programs linked to key morphogenetic milestones. We describe principles of crypt-villus axis formation; neural, vascular, mesenchymal morphogenesis, and immune population of the developing gut. We identify the differentiation hierarchies of developing fibroblast and myofibroblast subtypes and describe diverse functions for these including as vascular niche cells. We pinpoint the origins of Peyer's patches and gut-associated lymphoid tissue (GALT) and describe location-specific immune programs. We use our resource to present an unbiased analysis of morphogen gradients that direct sequential waves of cellular differentiation and define cells and locations linked to rare developmental intestinal disorders. We compile a publicly available online resource, spatio-temporal analysis resource of fetal intestinal development (STAR-FINDer), to facilitate further work.


Assuntos
Intestinos/citologia , Intestinos/crescimento & desenvolvimento , Análise de Célula Única , Células Endoteliais/citologia , Sistema Nervoso Entérico/citologia , Feto/embriologia , Fibroblastos/citologia , Humanos , Imunidade , Enteropatias/congênito , Enteropatias/patologia , Mucosa Intestinal/crescimento & desenvolvimento , Intestinos/irrigação sanguínea , Ligantes , Mesoderma/citologia , Neovascularização Fisiológica , Pericitos/citologia , Células-Tronco/citologia , Fatores de Tempo , Fatores de Transcrição/metabolismo
7.
Cell ; 184(20): 5230-5246.e22, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34551315

RESUMO

Although mutations leading to a compromised nuclear envelope cause diseases such as muscular dystrophies or accelerated aging, the consequences of mechanically induced nuclear envelope ruptures are less known. Here, we show that nuclear envelope ruptures induce DNA damage that promotes senescence in non-transformed cells and induces an invasive phenotype in human breast cancer cells. We find that the endoplasmic reticulum (ER)-associated exonuclease TREX1 translocates into the nucleus after nuclear envelope rupture and is required to induce DNA damage. Inside the mammary duct, cellular crowding leads to nuclear envelope ruptures that generate TREX1-dependent DNA damage, thereby driving the progression of in situ carcinoma to the invasive stage. DNA damage and nuclear envelope rupture markers were also enriched at the invasive edge of human tumors. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Dano ao DNA , Exodesoxirribonucleases/metabolismo , Membrana Nuclear/metabolismo , Fosfoproteínas/metabolismo , Animais , Linhagem Celular , Senescência Celular , Colágeno/metabolismo , Progressão da Doença , Feminino , Humanos , Camundongos , Invasividade Neoplásica , Membrana Nuclear/ultraestrutura , Proteólise , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cell ; 179(6): 1289-1305.e21, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31761534

RESUMO

Adult mesenchymal stem cells, including preadipocytes, possess a cellular sensory organelle called the primary cilium. Ciliated preadipocytes abundantly populate perivascular compartments in fat and are activated by a high-fat diet. Here, we sought to understand whether preadipocytes use their cilia to sense and respond to external cues to remodel white adipose tissue. Abolishing preadipocyte cilia in mice severely impairs white adipose tissue expansion. We discover that TULP3-dependent ciliary localization of the omega-3 fatty acid receptor FFAR4/GPR120 promotes adipogenesis. FFAR4 agonists and ω-3 fatty acids, but not saturated fatty acids, trigger mitosis and adipogenesis by rapidly activating cAMP production inside cilia. Ciliary cAMP activates EPAC signaling, CTCF-dependent chromatin remodeling, and transcriptional activation of PPARγ and CEBPα to initiate adipogenesis. We propose that dietary ω-3 fatty acids selectively drive expansion of adipocyte numbers to produce new fat cells and store saturated fatty acids, enabling homeostasis of healthy fat tissue.


Assuntos
Adipogenia , Cílios/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Fator de Ligação a CCCTC/metabolismo , Cromatina/metabolismo , Cílios/efeitos dos fármacos , AMP Cíclico/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/metabolismo
9.
Cell ; 173(5): 1150-1164.e14, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29706544

RESUMO

Tandem repeats (TRs) are generated by DNA replication errors and retain a high level of instability, which in principle would make them unsuitable for integration into gene regulatory networks. However, the appearance of DNA sequence motifs recognized by transcription factors may turn TRs into functional cis-regulatory elements, thus favoring their stabilization in genomes. Here, we show that, in human cells, the transcriptional repressor ZEB1, which promotes the maintenance of mesenchymal features largely by suppressing epithelial genes and microRNAs, occupies TRs harboring dozens of copies of its DNA-binding motif within genomic loci relevant for maintenance of epithelial identity. The deletion of one such TR caused quasi-mesenchymal cancer cells to reacquire epithelial features, partially recapitulating the effects of ZEB1 gene deletion. These data demonstrate that the high density of identical motifs in TRs can make them suitable platforms for recruitment of transcriptional repressors, thus promoting their exaptation into pre-existing cis-regulatory networks.


Assuntos
Sequências de Repetição em Tandem/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Adulto , Animais , Sequência de Bases , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Feminino , Expressão Gênica , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Mucosa Bucal/metabolismo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Fatores de Transcrição/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/deficiência , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
10.
Immunity ; 56(6): 1204-1219.e8, 2023 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-37160119

RESUMO

During development, lymph node (LN) initiation is coordinated by lymphoid tissue organizer (LTo) cells that attract lymphoid tissue inducer (LTi) cells at strategic positions within the embryo. The identity and function of LTo cells during the initial attraction of LTi cells remain poorly understood. Using lineage tracing, we demonstrated that a subset of Osr1-expressing cells was mesenchymal LTo progenitors. By investigating the heterogeneity of Osr1+ cells, we uncovered distinct mesenchymal LTo signatures at diverse anatomical locations, identifying a common progenitor of mesenchymal LTos and LN-associated adipose tissue. Osr1 was essential for LN initiation, driving the commitment of mesenchymal LTo cells independent of neural retinoic acid, and for LN-associated lymphatic vasculature assembly. The combined action of chemokines CXCL13 and CCL21 was required for LN initiation. Our results redefine the role and identity of mesenchymal organizer cells and unify current views by proposing a model of cooperative cell function in LN initiation.


Assuntos
Organogênese , Fatores de Transcrição , Diferenciação Celular , Linfonodos , Tecido Linfoide
11.
Cell ; 168(3): 362-375, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28129537

RESUMO

The immune system safeguards organ integrity by employing a balancing act of inflammatory and immunosuppressive mechanisms designed to neutralize foreign invaders and resolve injury. Maintaining or restoring a state of immune homeostasis is particularly challenging at barrier sites where constant exposure to immunogenic environmental agents may induce destructive inflammation. Recent studies underscore the role of epithelial and mesenchymal barrier cells in regulating immune cell function and local homeostatic and inflammatory responses. Here, we highlight immunoregulatory circuits engaging epithelial and mesenchymal cells in the intestine, airways, and skin and discuss how immune communications with hematopoietic cells and the microbiota orchestrate local immune homeostasis and inflammation.


Assuntos
Epitélio/imunologia , Homeostase , Inflamação/imunologia , Mesoderma/imunologia , Animais , Células Epiteliais/imunologia , Humanos , Infecções/imunologia , Intestinos/citologia , Intestinos/imunologia , Intestinos/fisiologia , Mesoderma/citologia , Sistema Respiratório/imunologia
12.
Cell ; 169(3): 483-496.e13, 2017 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-28413068

RESUMO

Adult tissue stem cells (SCs) reside in niches, which, through intercellular contacts and signaling, influence SC behavior. Once activated, SCs typically give rise to short-lived transit-amplifying cells (TACs), which then progress to differentiate into their lineages. Here, using single-cell RNA-seq, we unearth unexpected heterogeneity among SCs and TACs of hair follicles. We trace the roots of this heterogeneity to micro-niches along epithelial-mesenchymal interfaces, where progenitors display molecular signatures reflective of spatially distinct local signals and intercellular interactions. Using lineage tracing, temporal single-cell analyses, and chromatin landscaping, we show that SC plasticity becomes restricted in a sequentially and spatially choreographed program, culminating in seven spatially arranged unilineage progenitors within TACs of mature follicles. By compartmentalizing SCs into micro-niches, tissues gain precise control over morphogenesis and regeneration: some progenitors specify lineages immediately, whereas others retain potency, preserving self-renewing features established early while progressively restricting lineages as they experience dynamic changes in microenvironment.


Assuntos
Células-Tronco Adultas/citologia , Linhagem da Célula , Folículo Piloso/citologia , Nicho de Células-Tronco , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Análise de Célula Única , Via de Sinalização Wnt
13.
Cell ; 170(6): 1149-1163.e12, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28886383

RESUMO

The diversity of mesenchymal cell types in the lung that influence epithelial homeostasis and regeneration is poorly defined. We used genetic lineage tracing, single-cell RNA sequencing, and organoid culture approaches to show that Lgr5 and Lgr6, well-known markers of stem cells in epithelial tissues, are markers of mesenchymal cells in the adult lung. Lgr6+ cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia and promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6+ cells impairs airway injury repair in vivo. Distinct Lgr5+ cells are located in alveolar compartments and are sufficient to promote alveolar differentiation of epithelial progenitors through Wnt activation. Modulating Wnt activity altered differentiation outcomes specified by mesenchymal cells. This identification of region- and lineage-specific crosstalk between epithelium and their neighboring mesenchymal partners provides new understanding of how different cell types are maintained in the adult lung.


Assuntos
Pulmão/citologia , Mesoderma/citologia , Animais , Homeostase , Pulmão/fisiologia , Camundongos , Organoides/citologia , Alvéolos Pulmonares/citologia , Receptores Acoplados a Proteínas G/análise , Análise de Sequência de RNA , Análise de Célula Única , Transcrição Gênica
14.
Cell ; 171(7): 1611-1624.e24, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29198524

RESUMO

The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of ∼6,000 single cells from 18 head and neck squamous cell carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined HNSCC subtypes by their malignant and stromal composition and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Metástase Neoplásica/patologia , Carcinoma de Células Escamosas/genética , Células Cultivadas , Transição Epitelial-Mesenquimal , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Análise de Célula Única , Microambiente Tumoral
15.
Genes Dev ; 38(5-6): 273-288, 2024 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-38589034

RESUMO

Glioblastoma is universally fatal and characterized by frequent chromosomal copy number alterations harboring oncogenes and tumor suppressors. In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR-Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate PDE10A as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expression led to increased PI3K/AKT signaling in a Pten-independent manner, a response blocked by selective PI3K inhibitors. Single-nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation, further showed that Pde10a suppression was associated with a proneural-to-mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. Our results indicate that glioblastoma patients harboring PDE10A loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Animais , Camundongos , Glioblastoma/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Haploinsuficiência , Glioma/genética , PTEN Fosfo-Hidrolase/genética , Diester Fosfórico Hidrolases/genética , Linhagem Celular Tumoral , Neoplasias Encefálicas/genética
16.
Physiol Rev ; 104(2): 659-725, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37589393

RESUMO

Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.


Assuntos
Insuficiência Cardíaca , Células-Tronco Mesenquimais , Infarto do Miocárdio , Humanos , Infarto do Miocárdio/terapia , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Fenômenos Fisiológicos Cardiovasculares , Insuficiência Cardíaca/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia
17.
Immunity ; 55(5): 862-878.e8, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35508166

RESUMO

Macrophage colony stimulating factor-1 (CSF-1) plays a critical role in maintaining myeloid lineage cells. However, congenital global deficiency of CSF-1 (Csf1op/op) causes severe musculoskeletal defects that may indirectly affect hematopoiesis. Indeed, we show here that osteolineage-derived Csf1 prevented developmental abnormalities but had no effect on monopoiesis in adulthood. However, ubiquitous deletion of Csf1 conditionally in adulthood decreased monocyte survival, differentiation, and migration, independent of its effects on bone development. Bone histology revealed that monocytes reside near sinusoidal endothelial cells (ECs) and leptin receptor (Lepr)-expressing perivascular mesenchymal stromal cells (MSCs). Targeted deletion of Csf1 from sinusoidal ECs selectively reduced Ly6C- monocytes, whereas combined depletion of Csf1 from ECs and MSCs further decreased Ly6Chi cells. Moreover, EC-derived CSF-1 facilitated recovery of Ly6C- monocytes and protected mice from weight loss following induction of polymicrobial sepsis. Thus, monocytes are supported by distinct cellular sources of CSF-1 within a perivascular BM niche.


Assuntos
Fator Estimulador de Colônias de Macrófagos , Células-Tronco Mesenquimais , Animais , Medula Óssea , Células da Medula Óssea , Células Endoteliais , Fator Estimulador de Colônias de Macrófagos/farmacologia , Camundongos , Monócitos
18.
Cell ; 166(1): 21-45, 2016 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-27368099

RESUMO

The significant parallels between cell plasticity during embryonic development and carcinoma progression have helped us understand the importance of the epithelial-mesenchymal transition (EMT) in human disease. Our expanding knowledge of EMT has led to a clarification of the EMT program as a set of multiple and dynamic transitional states between the epithelial and mesenchymal phenotypes, as opposed to a process involving a single binary decision. EMT and its intermediate states have recently been identified as crucial drivers of organ fibrosis and tumor progression, although there is some need for caution when interpreting its contribution to metastatic colonization. Here, we discuss the current state-of-the-art and latest findings regarding the concept of cellular plasticity and heterogeneity in EMT. We raise some of the questions pending and identify the challenges faced in this fast-moving field.


Assuntos
Transição Epitelial-Mesenquimal , Fibrose/patologia , Neoplasias/patologia , Animais , Desenvolvimento Embrionário , Epigênese Genética , Humanos , Transcrição Gênica
19.
Genes Dev ; 37(17-18): 781-800, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37798016

RESUMO

Adipose tissue exhibits a remarkable capacity to expand, contract, and remodel in response to changes in physiological and environmental conditions. Here, we describe recent advances in our understanding of how functionally distinct tissue-resident mesenchymal stromal cell subpopulations orchestrate several aspects of physiological and pathophysiological adipose tissue remodeling, with a particular focus on the adaptations that occur in response to changes in energy surplus and environmental temperature. The study of adipose tissue remodeling provides a vehicle to understand the functional diversity of stromal cells and offers a lens through which several generalizable aspects of tissue reorganization can be readily observed.


Assuntos
Adipogenia , Células-Tronco Mesenquimais , Humanos , Tecido Adiposo , Obesidade , Células Estromais
20.
Physiol Rev ; 103(3): 1899-1964, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36656056

RESUMO

The teeth are vertebrate-specific, highly specialized organs performing fundamental functions of mastication and speech, the maintenance of which is crucial for orofacial homeostasis and is further linked to systemic health and human psychosocial well-being. However, with limited ability for self-repair, the teeth can often be impaired by traumatic, inflammatory, and progressive insults, leading to high prevalence of tooth loss and defects worldwide. Regenerative medicine holds the promise to achieve physiological restoration of lost or damaged organs, and in particular an evolving framework of developmental engineering has pioneered functional tooth regeneration by harnessing the odontogenic program. As a key event of tooth morphogenesis, mesenchymal condensation dictates dental tissue formation and patterning through cellular self-organization and signaling interaction with the epithelium, which provides a representative to decipher organogenetic mechanisms and can be leveraged for regenerative purposes. In this review, we summarize how mesenchymal condensation spatiotemporally assembles from dental stem cells (DSCs) and sequentially mediates tooth development. We highlight condensation-mimetic engineering efforts and mechanisms based on ex vivo aggregation of DSCs, which have achieved functionally robust and physiologically relevant tooth regeneration after implantation in animals and in humans. The discussion of this aspect will add to the knowledge of development-inspired tissue engineering strategies and will offer benefits to propel clinical organ regeneration.


Assuntos
Regeneração Óssea , Mesoderma , Odontogênese , Engenharia Tecidual , Perda de Dente , Dente , Dente/crescimento & desenvolvimento , Engenharia Tecidual/métodos , Humanos , Animais , Mesoderma/crescimento & desenvolvimento , Perda de Dente/terapia
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