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1.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502088

RESUMO

We aimed to investigate the spatio-temporal expression of possible CAKUT candidate genes CRKL, AIFM3, and UBASH3A, as well as AIF and BCL2 during human kidney development. Human fetal kidney tissue was stained with antibodies and analyzed by fluorescence microscopy and RT-PCR. Quantification of positive cells was assessed by calculation of area percentage and counting cells in nephron structures. Results showed statistically significant differences in the temporal expression patterns of the examined markers, depending on the investigated developmental stage. Limited but strong expression of CRKL was seen in developing kidneys, with increasing expression up to the period where the majority of nephrons are formed. Results also lead us to conclude that AIFM3 and AIF are important for promoting cell survival, but only AIFM3 is considered a CAKUT candidate gene due to the lack of AIF in nephron developmental structures. Our findings imply great importance of AIFM3 in energy production in nephrogenesis and tubular maturation. UBASH3A raw scores showed greater immunoreactivity in developing structures than mature ones which would point to a meaningful role in nephrogenesis. The fact that mRNA and proteins of CRKL, UBASH3A, and AIFM3 were detected in all phases of kidney development implies their role as renal development control genes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Rim/metabolismo , Proteínas Mitocondriais/genética , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fator de Indução de Apoptose/genética , Fator de Indução de Apoptose/metabolismo , Feto/embriologia , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lactente , Recém-Nascido , Rim/embriologia , Rim/crescimento & desenvolvimento , Proteínas Mitocondriais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
2.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361023

RESUMO

Aging is an unavoidable part of life. The more aged we become, the more susceptible we become to various complications and damages to the vital organs, including the kidneys. The existing drugs for kidney diseases are mostly of synthetic origins; thus, natural compounds with minimal side-effects have attracted growing interest from the scientific community and pharmaceutical companies. A literature search was carried out to collect published research information on the effects of resveratrol on kidney aging. Recently, resveratrol has emerged as a potential anti-aging agent. This versatile polyphenol exerts its anti-aging effects by intervening in various pathologies and multi-signaling systems, including sirtuin type 1, AMP-activated protein kinase, and nuclear factor-κB. Researchers are trying to figure out the detailed mechanisms and possible resveratrol-mediated interventions in divergent pathways at the molecular level. This review highlights (i) the causative factors implicated in kidney aging and the therapeutic aspects of resveratrol, and (ii) the effectiveness of resveratrol in delaying the aging process of the kidney while minimizing all possible side effects.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Rim/efeitos dos fármacos , Resveratrol/farmacologia , Envelhecimento/metabolismo , Animais , Humanos , Rim/crescimento & desenvolvimento , Rim/metabolismo , Sirtuína 1/metabolismo
3.
Nat Commun ; 12(1): 3641, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131121

RESUMO

Current kidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney's collecting duct (CD) system. Here, we report the generation of an expandable, 3D branching ureteric bud (UB) organoid culture model that can be derived from primary UB progenitors from mouse and human fetal kidneys, or generated de novo from human pluripotent stem cells. In chemically-defined culture conditions, UB organoids generate CD organoids, with differentiated principal and intercalated cells adopting spatial assemblies reflective of the adult kidney's collecting system. Aggregating 3D-cultured nephron progenitor cells with UB organoids in vitro results in a reiterative process of branching morphogenesis and nephron induction, similar to kidney development. Applying an efficient gene editing strategy to remove RET activity, we demonstrate genetically modified UB organoids can model congenital anomalies of kidney and urinary tract. Taken together, these platforms will facilitate an enhanced understanding of development, regeneration and diseases of the mammalian collecting duct system.


Assuntos
Túbulos Renais Coletores/citologia , Rim/citologia , Rim/crescimento & desenvolvimento , Organogênese/fisiologia , Organoides/citologia , Organoides/crescimento & desenvolvimento , Ureter , Sistema Urinário/citologia , Adulto , Animais , Diferenciação Celular , Células Cultivadas , Humanos , Rim/embriologia , Túbulos Renais Coletores/embriologia , Masculino , Camundongos , Morfogênese , Néfrons , Organogênese/genética , Organoides/embriologia , Células-Tronco Pluripotentes/citologia , Sistema Urinário/embriologia , Sistema Urinário/crescimento & desenvolvimento
4.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070742

RESUMO

Nephrogenesis is driven by complex signaling pathways that control cell growth and differentiation. The endoplasmic reticulum chaperone calreticulin (Calr) is well known for its function in calcium storage and in the folding of glycoproteins. Its role in kidney development is still not understood. We provide evidence for a pivotal role of Calr in nephrogenesis in this investigation. We show that Calr deficiency results in the disrupted formation of an intact nephrogenic zone and in retardation of nephrogenesis, as evidenced by the disturbance in the formation of comma-shaped and s-shaped bodies. Using proteomics and transcriptomics approaches, we demonstrated that in addition to an alteration in Wnt-signaling key proteins, embryonic kidneys from Calr-/- showed an overall impairment in expression of ribosomal proteins which reveals disturbances in protein synthesis and nephrogenesis. CRISPR/cas9 mediated knockout confirmed that Calr deficiency is associated with a deficiency of several ribosomal proteins and key proteins in ribosome biogenesis. Our data highlights a direct link between Calr expression and the ribosome biogenesis.


Assuntos
Cálcio/metabolismo , Calreticulina/genética , Rim/metabolismo , Biogênese de Organelas , Proteínas Ribossômicas/genética , Ribossomos/genética , Animais , Sinalização do Cálcio , Calreticulina/deficiência , Embrião de Mamíferos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Glicoproteínas/classificação , Glicoproteínas/genética , Glicoproteínas/metabolismo , Rim/crescimento & desenvolvimento , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Organogênese/genética , Dobramento de Proteína , Proteômica/métodos , Proteínas Ribossômicas/deficiência , Ribossomos/metabolismo , Ribossomos/patologia , Via de Sinalização Wnt
5.
Am J Physiol Renal Physiol ; 320(6): F1106-F1122, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33938239

RESUMO

Ksp-cadherin (cadherin-16) is an atypical member of the cadherin superfamily of cell adhesion molecules that is ubiquitously expressed on the basolateral membrane of epithelial cells lining the nephron and the collecting system of the mammalian kidney. The principal aim of the present study was to determine if Ksp-cadherin played a critical role in the development and maintenance of the adult mammalian kidney by generating and evaluating a mouse line deficient in Ksp-cadherin. Ksp-null mutant animals were viable and fertile, and kidneys from both neonates and adults showed no evidence of structural abnormalities. Immunolocalization and Western blot analyses of Na+-K+-ATPase and E-cadherin indicated that Ksp-cadherin is not essential for either the genesis or maintenance of the polarized tubular epithelial phenotype. Moreover, E-cadherin expression was not altered to compensate for Ksp-cadherin loss. Plasma electrolytes, total CO2, blood urea nitrogen, and creatinine levels were also unaffected by Ksp-cadherin deficiency. However, a subtle but significant developmental delay in the ability to maximally concentrate urine was detected in Ksp-null mice. Expression analysis of the principal proteins involved in the generation of the corticomedullary osmotic gradient and the resultant movement of water identified misexpression of aquaporin-2 in the inner medullary collecting duct as the possible cause for the inability of young adult Ksp-cadherin-deficient animals to maximally concentrate their urine. In conclusion, Ksp-cadherin is not required for normal kidney development, but its absence leads to a developmental delay in maximal urinary concentrating ability.NEW & NOTEWORTHY Ksp-cadherin (cadherin-16) is an atypical member of the cadherin superfamily of cell adhesion molecules that is ubiquitously expressed on the basolateral membrane of epithelial cells lining the nephron and the collecting system. Using knockout mice, we found that Ksp-cadherin is in fact not required for kidney development despite its high and specific expression along the nephron. However, its absence leads to a developmental delay in maximal urinary concentrating ability.


Assuntos
Caderinas/metabolismo , Capacidade de Concentração Renal/fisiologia , Rim/crescimento & desenvolvimento , Animais , Aquaporina 2/genética , Aquaporina 2/metabolismo , Caderinas/genética , Regulação da Expressão Gênica no Desenvolvimento , Rim/fisiologia , Capacidade de Concentração Renal/genética , Masculino , Camundongos , Camundongos Knockout , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo
6.
Development ; 148(9)2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33946098

RESUMO

During lung development, epithelial branches expand preferentially in a longitudinal direction. This bias in outgrowth has been linked to a bias in cell shape and in the cell division plane. How this bias arises is unknown. Here, we show that biased epithelial outgrowth occurs independent of the surrounding mesenchyme, of preferential turnover of the extracellular matrix at the bud tips and of FGF signalling. There is also no evidence for actin-rich filopodia at the bud tips. Rather, we find epithelial tubes to be collapsed during early lung and kidney development, and we observe fluid flow in the narrow tubes. By simulating the measured fluid flow inside segmented narrow epithelial tubes, we show that the shear stress levels on the apical surface are sufficient to explain the reported bias in cell shape and outgrowth. We use a cell-based vertex model to confirm that apical shear forces, unlike constricting forces, can give rise to both the observed bias in cell shapes and tube elongation. We conclude that shear stress may be a more general driver of biased tube elongation beyond its established role in angiogenesis. This article has an associated 'The people behind the papers' interview.


Assuntos
Fenômenos Biomecânicos , Rim/crescimento & desenvolvimento , Pulmão/crescimento & desenvolvimento , Organogênese , Animais , Biofísica , Forma Celular , Células Epiteliais/citologia , Matriz Extracelular , Feminino , Masculino , Mesoderma/metabolismo , Camundongos , Modelos Biológicos , Morfogênese , Pseudópodes
7.
Development ; 148(9)2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33914865

RESUMO

Ret signaling promotes branching morphogenesis during kidney development, but the underlying cellular mechanisms remain unclear. While Ret-expressing progenitor cells proliferate at the ureteric bud tips, some of these cells exit the tips to generate the elongating collecting ducts, and in the process turn off Ret. Genetic ablation of Ret in tip cells promotes their exit, suggesting that Ret is required for cell rearrangements that maintain the tip compartments. Here, we examine the behaviors of ureteric bud cells that are genetically forced to maintain Ret expression. These cells move to the nascent tips, and remain there during many cycles of branching; this tip-seeking behavior may require positional signals from the mesenchyme, as it occurs in whole kidneys but not in epithelial ureteric bud organoids. In organoids, cells forced to express Ret display a striking self-organizing behavior, attracting each other to form dense clusters within the epithelium, which then evaginate to form new buds. The ability of forced Ret expression to promote these events suggests that similar Ret-dependent cell behaviors play an important role in normal branching morphogenesis.


Assuntos
Movimento Celular , Células Epiteliais/metabolismo , Transdução de Sinais , Ureter/metabolismo , Animais , Análise por Conglomerados , Epitélio/metabolismo , Feminino , Rim/crescimento & desenvolvimento , Rim/metabolismo , Masculino , Mesoderma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Morfogênese , Organoides , Proteínas Tirosina Quinases/metabolismo , Células-Tronco/metabolismo
9.
Am J Med Genet A ; 185(5): 1554-1560, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33645921

RESUMO

POU3F3 proteins are eukaryotic transcription factors and contribute to the processes in the development of brain and kidney. Pathogenic POU3F3 variants cause a neurodevelopmental disorder called Snijders Blok-Fisher syndrome (SNIBFIS). This article reports a new SNIBFIS case harboring a novel heterozygous c.1018_1019delCAinsTT (p.Gln340Leu) variant in the POU3F3 gene. This variant affects the α2 helix of POU-S domain and is predicted to be "pathogenic" by multiple in-silico tools. The proband had severe intellectual disability, hypotonia, autistic features, sleep disturbances, and dysmorphic features. The association with epilepsy and hemangioma like two of the three previously reported patients with mutations in the POU-S domain was also a remarkable finding to understand the importance of POU-S domain. This clinical report also highlights the interest of reinterpretation of molecular data and brings a new perspective to the genotype-phenotype relationship in "Snijders Blok-Fisher syndrome".


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Hemangioma/genética , Fatores do Domínio POU/genética , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/patologia , Epilepsia/complicações , Epilepsia/diagnóstico , Epilepsia/patologia , Estudos de Associação Genética , Hemangioma/complicações , Hemangioma/diagnóstico , Hemangioma/patologia , Humanos , Rim/crescimento & desenvolvimento , Rim/patologia , Fatores do Domínio POU/ultraestrutura , Conformação Proteica em alfa-Hélice/genética
10.
Genes (Basel) ; 12(2)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33672414

RESUMO

The adult mammalian kidney is a poorly regenerating organ that lacks the stem cells that could replenish functional homeostasis similarly to, e.g., skin or the hematopoietic system. Unlike a mature kidney, the embryonic kidney hosts at least three types of lineage-specific stem cells that give rise to (a) a ureter and collecting duct system, (b) nephrons, and (c) mesangial cells together with connective tissue of the stroma. Extensive interest has been raised towards these embryonic progenitor cells, which are normally lost before birth in humans but remain part of the undifferentiated nephrogenic rests in the pediatric renal cancer Wilms tumor. Here, we discuss the current understanding of kidney-specific embryonic progenitor regulation in the innate environment of the developing kidney and the types of disruptions in their balanced regulation that lead to the formation of Wilms tumor.


Assuntos
Desenvolvimento Embrionário/genética , Rim/crescimento & desenvolvimento , Organogênese/genética , Tumor de Wilms/genética , Animais , Diferenciação Celular/genética , Criança , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/patologia , Humanos , Rim/patologia , Tumor de Wilms/patologia
11.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33669059

RESUMO

The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.


Assuntos
Hipertensão/metabolismo , Nefropatias/metabolismo , Rim/crescimento & desenvolvimento , Néfrons/crescimento & desenvolvimento , Sistema Renina-Angiotensina , Renina/metabolismo , Adulto , Animais , Modelos Animais de Doenças , Disbiose/metabolismo , Epigênese Genética , Humanos , Hipertensão/genética , Rim/metabolismo , Nefropatias/enzimologia , Nefropatias/genética , Néfrons/citologia , Néfrons/metabolismo , Óxido Nítrico/deficiência , Óxido Nítrico/metabolismo , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia
12.
Nat Rev Nephrol ; 17(6): 369-385, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33547419

RESUMO

Planar cell polarity (PCP) refers to the coordinated orientation of cells in the tissue plane. Originally discovered and studied in Drosophila melanogaster, PCP is now widely recognized in vertebrates, where it is implicated in organogenesis. Specific sets of PCP genes have been identified. The proteins encoded by these genes become asymmetrically distributed to opposite sides of cells within a tissue plane and guide many processes that include changes in cell shape and polarity, collective cell movements or the uniform distribution of cell appendages. A unifying characteristic of these processes is that they often involve rearrangement of actomyosin. Mutations in PCP genes can cause malformations in organs of many animals, including humans. In the past decade, strong evidence has accumulated for a role of the PCP pathway in kidney development including outgrowth and branching morphogenesis of ureteric bud and podocyte development. Defective PCP signalling has been implicated in the pathogenesis of developmental kidney disorders of the congenital anomalies of the kidney and urinary tract spectrum. Understanding the origins, molecular constituents and cellular targets of PCP provides insights into the involvement of PCP molecules in normal kidney development and how dysfunction of PCP components may lead to kidney disease.


Assuntos
Polaridade Celular/fisiologia , Nefropatias/etiologia , Rim/crescimento & desenvolvimento , Animais , Drosophila/crescimento & desenvolvimento , Humanos , Rim/embriologia , Rim/fisiologia , Nefropatias/fisiopatologia , Transdução de Sinais/fisiologia
13.
Life Sci Alliance ; 4(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33574034

RESUMO

Compensatory growth of organs after loss of their mass and/or function is controlled by hepatocyte growth factor (HGF), but the underlying regulatory mechanisms remain elusive. Here, we show that CUB domain-containing protein 1 (CDCP1) promotes HGF-induced compensatory renal growth. Using canine kidney cells as a model of renal tubules, we found that HGF-induced temporal up-regulation of Src activity and its scaffold protein, CDCP1, and that the ablation of CDCP1 robustly abrogated HGF-induced phenotypic changes, such as morphological changes and cell growth/proliferation. Mechanistic analyses revealed that up-regulated CDCP1 recruits Src into lipid rafts to activate STAT3 associated with the HGF receptor Met, and activated STAT3 induces the expression of matrix metalloproteinases and mitogenic factors. After unilateral nephrectomy in mice, the Met-STAT3 signaling is transiently up-regulated in the renal tubules of the remaining kidney, whereas CDCP1 ablation attenuates regenerative signaling and significantly suppresses compensatory growth. These findings demonstrate that CDCP1 plays a crucial role in controlling compensatory renal growth by focally and temporally integrating Src and Met signaling.


Assuntos
Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Rim/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais , Quinases da Família src/metabolismo , Animais , Linhagem Celular , Imunofluorescência , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Rim/crescimento & desenvolvimento , Microdomínios da Membrana/metabolismo , Camundongos , Camundongos Knockout , Fosforilação , Ligação Proteica , Fator de Transcrição STAT3/metabolismo
14.
Am J Physiol Regul Integr Comp Physiol ; 320(4): R377-R383, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33470188

RESUMO

(Pro)renin receptor (PRR), a 350-amino acid receptor initially thought of as a receptor for the binding of renin and prorenin, is multifunctional. In addition to its role in the renin-angiotensin system (RAS), PRR transduces several intracellular signaling molecules and is a component of the vacuolar H+-ATPase that participates in autophagy. PRR is found in the kidney and particularly in great abundance in the cortical collecting duct. In the kidney, PRR participates in water and salt balance, acid-base balance, and autophagy and plays a role in development and progression of hypertension, diabetic retinopathy, and kidney fibrosis. This review highlights the role of PRR in the development and function of the kidney, namely, the macula densa, podocyte, proximal and distal convoluted tubule, and the principal cells of the collecting duct, and focuses on PRR function in body fluid volume homeostasis, blood pressure regulation, and acid-base balance. This review also explores new advances in the molecular mechanism involving PRR in normal renal health and pathophysiological states.


Assuntos
Equilíbrio Ácido-Base , Pressão Sanguínea , Rim/metabolismo , Receptores de Superfície Celular/metabolismo , Sistema Renina-Angiotensina , Equilíbrio Hidroeletrolítico , Animais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Fibrose , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Rim/crescimento & desenvolvimento , Rim/patologia , Estado de Hidratação do Organismo , Organogênese , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais
15.
Phys Biol ; 18(2): 026005, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33395673

RESUMO

An important feature of the branch morphogenesis during kidney development is the termination of the tips on the outer surface of a kidney. This feature requires the avoidance of the intersection between the tips and existing ducts inside the kidney. Here, we started from a continuous model and implemented the coarse grained rules into a fast and discrete simulations. The ligand-receptor-based Turing mechanism suggests a repulsion that decreases exponentially with distance between interacting branches, preventing the intersection between neighboring branches. We considered this repulsive effect in numerical simulations and successfully reproduce the key features of the experimentally observed branch morphology for an E15.5 kidney. We examine the similarity of several geometrical parameters between the simulation results and experimental observations. The good agreement between the simulations and experiments suggests that the concentration decay caused by the absorption of glial cell line derived neurotrophic factor might be the key factor to affect the geometry in early kidney development.


Assuntos
Rim/crescimento & desenvolvimento , Morfogênese , Transdução de Sinais , Animais , Rim/embriologia , Camundongos , Modelos Biológicos
16.
Immunogenetics ; 73(1): 53-63, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33426583

RESUMO

The function of a tissue is determined by its construction and cellular composition. The action of different genes can thus only be understood properly when seen in the context of the environment in which they are expressed and function. We now experience a renaissance in morphological research in fish, not only because, surprisingly enough, large structures have remained un-described until recently, but also because improved methods for studying morphological characteristics in combination with expression analysis are at hand. In this review, we address anatomical features of teleost immune tissues. There are approximately 30,000 known teleost fish species and only a minor portion of them have been studied. We aim our review at the Atlantic salmon (Salmo salar) and other salmonids, but when applicable, we also present information from other species. Our focus is the anatomy of the kidney, thymus, spleen, the interbranchial lymphoid tissue (ILT), the newly discovered salmonid cloacal bursa and the naso-pharynx associated lymphoid tissue (NALT).


Assuntos
Peixes/imunologia , Tecido Linfoide/anatomia & histologia , Animais , Peixes/anatomia & histologia , Peixes/crescimento & desenvolvimento , Brânquias/anatomia & histologia , Brânquias/crescimento & desenvolvimento , Brânquias/imunologia , Rim/anatomia & histologia , Rim/crescimento & desenvolvimento , Rim/imunologia , Tecido Linfoide/crescimento & desenvolvimento , Tecido Linfoide/imunologia , Nasofaringe/anatomia & histologia , Nasofaringe/crescimento & desenvolvimento , Nasofaringe/imunologia , Salmo salar/anatomia & histologia , Salmo salar/crescimento & desenvolvimento , Salmo salar/imunologia , Baço/anatomia & histologia , Baço/crescimento & desenvolvimento , Baço/imunologia , Timo/anatomia & histologia , Timo/crescimento & desenvolvimento , Timo/imunologia
17.
Dev Biol ; 470: 62-73, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33197428

RESUMO

Recent advances in stem cell biology have enabled the generation of kidney organoids in vitro, and further maturation of these organoids is observed after experimental transplantation. However, the current organoids remain immature and their precise maturation stages are difficult to determine because of limited information on developmental stage-dependent gene expressions in the kidney in vivo. To establish relevant molecular coordinates, we performed single-cell RNA sequencing (scRNA-seq) on developing kidneys at different stages in the mouse. By selecting genes that exhibited upregulation at birth compared with embryonic day 15.5 as well as cell lineage-specific expression, we generated gene lists correlated with developmental stages in individual cell lineages. Application of these lists to transplanted embryonic kidneys revealed that most cell types, other than the collecting ducts, exhibited similar maturation to kidneys at the neonatal stage in vivo, revealing non-synchronous maturation across the cell lineages. Thus, our scRNA-seq data can serve as useful molecular coordinates to assess the maturation of developing kidneys and eventually of kidney organoids.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Rim/crescimento & desenvolvimento , Rim/metabolismo , Animais , Animais Recém-Nascidos , Linhagem da Célula , Regulação para Baixo , Rim/citologia , Rim/embriologia , Glomérulos Renais/citologia , Glomérulos Renais/embriologia , Glomérulos Renais/crescimento & desenvolvimento , Glomérulos Renais/metabolismo , Transplante de Rim , Túbulos Renais/citologia , Túbulos Renais/embriologia , Túbulos Renais/crescimento & desenvolvimento , Túbulos Renais/metabolismo , Camundongos , Podócitos/citologia , Podócitos/metabolismo , RNA-Seq , Análise de Célula Única , Células-Tronco/citologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima
18.
Dev Biol ; 474: 22-36, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33333068

RESUMO

There is no doubt that the development of transplantable synthetic kidneys could improve the outcome for the many millions of people worldwide suffering from chronic kidney disease. Substantial progress has been made in the last 6 years in the generation of kidney tissue from stem cells. However, the limited scale, incomplete cellular complexity and functional immaturity of such structures suggests we are some way from this goal. While developmental biology has successfully guided advances to date, these human kidney models are limited in their capacity for ongoing nephrogenesis and lack corticomedullary definition, a unified vasculature and a coordinated exit path for urinary filtrate. This review will reassess our developmental understanding of how the mammalian embryo manages to create kidneys, how this has informed our progress to date and how both engineering and developmental biology can continue to guide us towards a synthetic kidney.


Assuntos
Rim/crescimento & desenvolvimento , Engenharia Tecidual/métodos , Animais , Humanos , Nefropatias/embriologia , Nefropatias/patologia , Organogênese , Organoides/crescimento & desenvolvimento , Biologia Sintética/métodos
19.
Methods Mol Biol ; 2230: 151-165, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33197014

RESUMO

Renal capsule transplantation is a very helpful method to grow embryonic tissues or tumors in a vascular environment, allowing for long-term engraftment and biological analyses. This chapter describes the surgical procedure for the transplantation of embryonic skeletal elements in the renal capsule of adult mice and points out the manipulations that can be applied for assaying the role of angiogenesis during bone development and repair.


Assuntos
Desenvolvimento Ósseo/genética , Transplante de Rim/métodos , Morfogênese/genética , Neovascularização Fisiológica/genética , Túnica Adventícia/crescimento & desenvolvimento , Túnica Adventícia/patologia , Animais , Epitélio/crescimento & desenvolvimento , Epitélio/patologia , Humanos , Rim/crescimento & desenvolvimento , Rim/patologia , Linfangiogênese/genética , Vasos Linfáticos/citologia , Camundongos , Neovascularização Patológica/genética , Organogênese/genética
20.
Sci Rep ; 10(1): 22097, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328501

RESUMO

In-vivo single cell clonal analysis in the adult mouse kidney has previously shown lineage-restricted clonal proliferation within varying nephron segments as a mechanism responsible for cell replacement and local regeneration. To analyze ex-vivo clonal growth, we now preformed limiting dilution to generate genuine clonal cultures from one single human renal epithelial cell, which can give rise to up to 3.4 * 106 cells, and analyzed their characteristics using transcriptomics. A comparison between clonal cultures revealed restriction to either proximal or distal kidney sub-lineages with distinct cellular and molecular characteristics; rapidly amplifying de-differentiated clones and a stably proliferating cuboidal epithelial-appearing clones, respectively. Furthermore, each showed distinct molecular features including cell-cycle, epithelial-mesenchymal transition, oxidative phosphorylation, BMP signaling pathway and cell surface markers. In addition, analysis of clonal versus bulk cultures show early clones to be more quiescent, with elevated expression of renal developmental genes and overall reduction in renal identity markers, but with an overlapping expression of nephron segment identifiers and multiple identity. Thus, ex-vivo clonal growth mimics the in-vivo situation displaying lineage-restricted precursor characteristics of mature renal cells. These data suggest that for reconstruction of varying renal lineages with human adult kidney based organoid technology and kidney regeneration ex-vivo, use of multiple heterogeneous precursors is warranted.


Assuntos
Evolução Clonal/genética , Rim/crescimento & desenvolvimento , Mesoderma/crescimento & desenvolvimento , Regeneração/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Biologia Computacional , Células Epiteliais/citologia , Transição Epitelial-Mesenquimal/genética , Humanos , Rim/citologia , Mesoderma/metabolismo , Néfrons/crescimento & desenvolvimento , Néfrons/metabolismo , Cultura Primária de Células , Análise de Célula Única , Células-Tronco/citologia
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