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1.
Genome Res ; 34(3): 498-513, 2024 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-38508693

RESUMO

Hydractinia is a colonial marine hydroid that shows remarkable biological properties, including the capacity to regenerate its entire body throughout its lifetime, a process made possible by its adult migratory stem cells, known as i-cells. Here, we provide an in-depth characterization of the genomic structure and gene content of two Hydractinia species, Hydractinia symbiolongicarpus and Hydractinia echinata, placing them in a comparative evolutionary framework with other cnidarian genomes. We also generated and annotated a single-cell transcriptomic atlas for adult male H. symbiolongicarpus and identified cell-type markers for all major cell types, including key i-cell markers. Orthology analyses based on the markers revealed that Hydractinia's i-cells are highly enriched in genes that are widely shared amongst animals, a striking finding given that Hydractinia has a higher proportion of phylum-specific genes than any of the other 41 animals in our orthology analysis. These results indicate that Hydractinia's stem cells and early progenitor cells may use a toolkit shared with all animals, making it a promising model organism for future exploration of stem cell biology and regenerative medicine. The genomic and transcriptomic resources for Hydractinia presented here will enable further studies of their regenerative capacity, colonial morphology, and ability to distinguish self from nonself.


Assuntos
Genoma , Hidrozoários , Animais , Hidrozoários/genética , Evolução Molecular , Transcriptoma , Células-Tronco/metabolismo , Masculino , Filogenia , Análise de Célula Única/métodos
2.
bioRxiv ; 2023 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-37786714

RESUMO

Hydractinia is a colonial marine hydroid that exhibits remarkable biological properties, including the capacity to regenerate its entire body throughout its lifetime, a process made possible by its adult migratory stem cells, known as i-cells. Here, we provide an in-depth characterization of the genomic structure and gene content of two Hydractinia species, H. symbiolongicarpus and H. echinata, placing them in a comparative evolutionary framework with other cnidarian genomes. We also generated and annotated a single-cell transcriptomic atlas for adult male H. symbiolongicarpus and identified cell type markers for all major cell types, including key i-cell markers. Orthology analyses based on the markers revealed that Hydractinia's i-cells are highly enriched in genes that are widely shared amongst animals, a striking finding given that Hydractinia has a higher proportion of phylum-specific genes than any of the other 41 animals in our orthology analysis. These results indicate that Hydractinia's stem cells and early progenitor cells may use a toolkit shared with all animals, making it a promising model organism for future exploration of stem cell biology and regenerative medicine. The genomic and transcriptomic resources for Hydractinia presented here will enable further studies of their regenerative capacity, colonial morphology, and ability to distinguish self from non-self.

3.
Cell Rep ; 42(9): 113072, 2023 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-37676763

RESUMO

An ancient evolutionary innovation of a novel cell type, the stinging cell (cnidocyte), appeared >600 million years ago in the phylum Cnidaria (sea anemones, corals, hydroids, and jellyfish). A complex bursting nano-injector of venom, the cnidocyst, is embedded in cnidocytes and enables cnidarians to paralyze their prey and predators, contributing to this phylum's evolutionary success. In this work, we show that post-transcriptional regulation by a pan-cnidarian microRNA, miR-2022, is essential for biogenesis of these cells in the sea anemone Nematostella vectensis. By manipulation of miR-2022 levels in a transgenic reporter line of cnidocytes, followed by transcriptomics, single-cell data analysis, prey paralysis assays, and cell sorting of transgenic cnidocytes, we reveal that miR-2022 enables cnidocyte biogenesis in Nematostella, while exhibiting a conserved expression domain with its targets in cnidocytes of other cnidarian species. Thus, here we revealed a functional basis to the conservation of one of nature's most ancient microRNAs.

4.
EMBO J ; 42(15): e112934, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37708295

RESUMO

N6-methyldeoxyadenosine (6mA) is a chemical alteration of DNA, observed across all realms of life. Although the functions of 6mA are well understood in bacteria and protists, its roles in animal genomes have been controversial. We show that 6mA randomly accumulates in early embryos of the cnidarian Hydractinia symbiolongicarpus, with a peak at the 16-cell stage followed by clearance to background levels two cell cycles later, at the 64-cell stage-the embryonic stage at which zygotic genome activation occurs in this animal. Knocking down Alkbh1, a putative initiator of animal 6mA clearance, resulted in higher levels of 6mA at the 64-cell stage and a delay in the initiation of zygotic transcription. Our data are consistent with 6mA originating from recycled nucleotides of degraded m6A-marked maternal RNA postfertilization. Therefore, while 6mA does not function as an epigenetic mark in Hydractinia, its random incorporation into the early embryonic genome inhibits transcription. In turn, Alkbh1 functions as a genomic 6mA "cleaner," facilitating timely zygotic genome activation. Given the random nature of genomic 6mA accumulation and its ability to interfere with gene expression, defects in 6mA clearance may represent a hitherto unknown cause of various pathologies.


Assuntos
Cnidários , Animais , Genômica , Cinética , Epigenômica , Cognição
5.
Cell Rep ; 42(7): 112687, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37392741

RESUMO

Cell fate stability is essential to maintaining "law and order" in complex animals. However, high stability comes at the cost of reduced plasticity and, by extension, poor regenerative ability. This evolutionary trade-off has resulted in most modern animals being rather simple and regenerative or complex and non-regenerative. The mechanisms mediating cellular plasticity and allowing for regeneration remain unknown. We show that signals emitted by senescent cells can destabilize the differentiated state of neighboring somatic cells, reprogramming them into stem cells that are capable of driving whole-body regeneration in the cnidarian Hydractinia symbiolongicarpus. Pharmacological or genetic inhibition of senescence prevents reprogramming and regeneration. Conversely, induction of transient ectopic senescence in a regenerative context results in supernumerary stem cells and faster regeneration. We propose that senescence signaling is an ancient mechanism mediating cellular plasticity. Understanding the senescence environment that promotes cellular reprogramming could provide an avenue to enhance regeneration.


Assuntos
Cnidários , Animais , Reprogramação Celular , Senescência Celular/genética , Transdução de Sinais , Células-Tronco
6.
G3 (Bethesda) ; 2023 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-37294738

RESUMO

Hydractinia symbiolongicarpus is a pioneering model organism for stem cell biology, being one of only a few animals with adult pluripotent stem cells (known as i-cells). However, the unavailability of a chromosome-level genome assembly has hindered a comprehensive understanding of global gene regulatory mechanisms underlying the function and evolution of i-cells. Here, we report the first chromosome-level genome assembly of H. symbiolongicarpus (HSymV2.0) using PacBio HiFi long-read sequencing and Hi-C scaffolding. The final assembly is 483 Mb in total length with 15 chromosomes representing 99.8% of the assembly. Repetitive sequences were found to account for 296 Mb (61%) of the total genome; we provide evidence for at least two periods of repeat expansion in the past. A total of 25,825 protein-coding genes were predicted in this assembly, which include 93.1% of the metazoan Benchmarking Universal Single-Copy Orthologs (BUSCO) gene set. 92.8% (23,971 genes) of the predicted proteins were functionally annotated. The H. symbiolongicarpus genome showed a high degree of macrosynteny conservation with the Hydra vulgaris genome. This chromosome-level genome assembly of H. symbiolongicarpus will be an invaluable resource for the research community that enhances broad biological studies on this unique model organism.

7.
Curr Biol ; 33(10): 1883-1892.e3, 2023 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-37028430

RESUMO

In most animals, pluripotency is irreversibly lost post gastrulation. By this stage, all embryonic cells have already committed either to one of the somatic lineages (ectoderm, endoderm, or mesoderm) or to the germline. The lack of pluripotent cells in adult life may be linked to organismal aging. Cnidarians (corals and jellyfish) are an early branch of animals that do not succumb to age, but the developmental potential of their adult stem cells remains unclear. Here, we show that adult stem cells in the cnidarian Hydractinia symbiolongicarpus (known as i-cells) are pluripotent. We transplanted single i-cells from transgenic fluorescent donors to wild-type recipients and followed them in vivo in the translucent animals. Single engrafted i-cells self-renewed and contributed to all somatic lineages and gamete production, co-existing with and eventually displacing the allogeneic recipient's cells. Hence, a fully functional, sexually competent individual can derive from a single adult i-cell. Pluripotent i-cells enable regenerative, plant-like clonal growth in these animals.


Assuntos
Células-Tronco Adultas , Cnidários , Células-Tronco Pluripotentes , Animais , Diferenciação Celular , Células Germinativas
8.
Development ; 150(1)2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36633190

RESUMO

Many animals achieve sperm chromatin compaction and stabilisation by replacing canonical histones with sperm nuclear basic proteins (SNBPs) such as protamines during spermatogenesis. Hydrozoan cnidarians and echinoid sea urchins lack protamines and have evolved a distinctive family of sperm-specific histone H2Bs (spH2Bs) with extended N termini rich in SPK(K/R) motifs. Echinoid sperm packaging is regulated by spH2Bs. Their sperm is negatively buoyant and fertilises on the sea floor. Hydroid cnidarians undertake broadcast spawning but their sperm properties are poorly characterised. We show that Hydractinia echinata and H. symbiolongicarpus sperm chromatin possesses higher stability than somatic chromatin, with reduced accessibility to transposase Tn5 integration and to endonucleases in vitro. In contrast, nuclear dimensions are only moderately reduced in mature Hydractinia sperm. Ectopic expression of spH2B in the background of H2B.1 knockdown results in downregulation of global transcription and cell cycle arrest in embryos, without altering their nuclear density. Taken together, SPKK-containing spH2B variants act to stabilise chromatin and silence transcription in Hydractinia sperm with only limited chromatin compaction. We suggest that spH2Bs could contribute to sperm buoyancy as a reproductive adaptation.


Assuntos
Histonas , Hidrozoários , Animais , Masculino , Histonas/metabolismo , Cromatina/metabolismo , Hidrozoários/genética , Sêmen/metabolismo , Espermatozoides/metabolismo , Protaminas/metabolismo
9.
Elife ; 112022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35608899

RESUMO

Neurogenesis is the generation of neurons from stem cells, a process that is regulated by SoxB transcription factors (TFs) in many animals. Although the roles of these TFs are well understood in bilaterians, how their neural function evolved is unclear. Here, we use Hydractinia symbiolongicarpus, a member of the early-branching phylum Cnidaria, to provide insight into this question. Using a combination of mRNA in situ hybridization, transgenesis, gene knockdown, transcriptomics, and in vivo imaging, we provide a comprehensive molecular and cellular analysis of neurogenesis during embryogenesis, homeostasis, and regeneration in this animal. We show that SoxB genes act sequentially at least in some cases. Stem cells expressing Piwi1 and Soxb1, which have broad developmental potential, become neural progenitors that express Soxb2 before differentiating into mature neural cells. Knockdown of SoxB genes resulted in complex defects in embryonic neurogenesis. Hydractinia neural cells differentiate while migrating from the aboral to the oral end of the animal, but it is unclear whether migration per se or exposure to different microenvironments is the main driver of their fate determination. Our data constitute a rich resource for studies aiming at addressing this question, which is at the heart of understanding the origin and development of animal nervous systems.


Assuntos
Cnidários , Animais , Cnidários/genética , Sistema Nervoso , Neurogênese/genética , Neurônios , Células-Tronco
10.
Methods Mol Biol ; 2450: 419-436, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35359321

RESUMO

The ability to regenerate lost body parts is irregularly distributed among animals, with substantial differences in regenerative potential between and within metazoan phyla. It is widely believed that regenerative animal clades inherited some aspects of their capacity to regenerate from their common ancestors but have also evolved new mechanisms that are not shared with other regenerative animals. Therefore, to gain a broad understanding of animal regenerative mechanisms and evolution, a broad sampling approach is necessary. Unfortunately, only few regenerative animals have been established as laboratory models with protocols for functional gene studies. Here, we describe the methods to establish transgenic individuals of the marine cnidarian Hydractinia. We also provide methods for transient gene expression manipulation without modifying the genome of the animals.


Assuntos
Cnidários , Regeneração , Animais , Cnidários/fisiologia
11.
Evodevo ; 11: 7, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226598

RESUMO

Hydractinia, a genus of colonial marine cnidarians, has been used as a model organism for developmental biology and comparative immunology for over a century. It was this animal where stem cells and germ cells were first studied. However, protocols for efficient genetic engineering have only recently been established by a small but interactive community of researchers. The animal grows well in the lab, spawns daily, and its relatively short life cycle allows genetic studies. The availability of genomic tools and resources opens further opportunities for research using this animal. Its accessibility to experimental manipulation, growth- and cellular-plasticity, regenerative ability, and resistance to aging and cancer place Hydractinia as an emerging model for research in many biological and environmental disciplines.

12.
Science ; 367(6479): 757-762, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32054756

RESUMO

Clonal animals do not sequester a germ line during embryogenesis. Instead, they have adult stem cells that contribute to somatic tissues or gametes. How germ fate is induced in these animals, and whether this process is related to bilaterian embryonic germline induction, is unknown. We show that transcription factor AP2 (Tfap2), a regulator of mammalian germ lines, acts to commit adult stem cells, known as i-cells, to the germ cell fate in the clonal cnidarian Hydractinia symbiolongicarpus Tfap2 mutants lacked germ cells and gonads. Transplanted wild-type cells rescued gonad development but not germ cell induction in Tfap2 mutants. Forced expression of Tfap2 in i-cells converted them to germ cells. Therefore, Tfap2 is a regulator of germ cell commitment across germ line-sequestering and germ line-nonsequestering animals.


Assuntos
Células-Tronco Adultas/citologia , Gametogênese/fisiologia , Células Germinativas/citologia , Gônadas/embriologia , Hidrozoários/embriologia , Fator de Transcrição AP-2/fisiologia , Células-Tronco Adultas/metabolismo , Animais , Feminino , Gametogênese/genética , Regulação da Expressão Gênica no Desenvolvimento , Gônadas/citologia , Hidrozoários/citologia , Hidrozoários/genética , Masculino , Fator de Transcrição AP-2/genética
14.
BMC Genomics ; 19(1): 649, 2018 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-30176818

RESUMO

BACKGROUND: Hydractinia symbiolongicarpus, a colonial cnidarian, is a tractable model system for many cnidarian-specific and general biological questions. Until recently, tests of gene function in Hydractinia have relied on laborious forward genetic approaches, randomly integrated transgenes, or transient knockdown of mRNAs. RESULTS: Here, we report the use of CRISPR/Cas9 genome editing to generate targeted genomic insertions in H. symbiolonigcarpus. We used CRISPR/Cas9 to promote homologous recombination of two fluorescent reporters, eGFP and tdTomato, into the Eukaryotic elongation factor 1 alpha (Eef1a) locus. We demonstrate that the transgenes are expressed ubiquitously and are stable over two generations of breeding. We further demonstrate that CRISPR/Cas9 genome editing can be used to mark endogenous proteins with FLAG or StrepII-FLAG affinity tags to enable in vivo and ex vivo protein studies. CONCLUSIONS: This is the first account of CRISPR/Cas9 mediated knockins in Hydractinia and the first example of the germline transmission of a CRISPR/Cas9 inserted transgene in a cnidarian. The ability to precisely insert exogenous DNA into the Hydractinia genome will enable sophisticated genetic studies and further development of functional genomics tools in this understudied cnidarian model.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Técnicas de Introdução de Genes , Hidrozoários/genética , Fator 1 de Elongação de Peptídeos/genética , Animais , Vetores Genéticos , Recombinação Homóloga , Hidrozoários/crescimento & desenvolvimento , Transgenes
15.
Commun Integr Biol ; 11(2): 1-5, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30083285

RESUMO

Regeneration has long been known to occur in the cnidarian Hydractinia. This process refers to its ability to regrow structures, i.e a head, lost by injury, a phenomenon that depends on the migration of proliferative cells to the site of injury, and the formation of a blastema, a mass of undifferentiated cells that will restore the missing head tissues. In our study, we showed that members of SoxB transcription factors and HDACs are involved in the regulation of Hydractinia neurogenesis in tissue homeostasis and regeneration. Particularly, we revealed that knockdown of SoxB2 or Hdac2 (a class I HDAC) knockdown, or inhibition of HDAC activity, suppress head regeneration. Here, we show that SoxB2 knockdown, or the inhibition of HDACs activity by TSA, a HDAC Class I and II inhibitor, interfere with head regeneration by affecting the migration of proliferative cells and the formation of a proliferative blastema.

16.
Dev Biol ; 428(1): 224-231, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28601529

RESUMO

The function of Notch signaling was previously studied in two cnidarians, Hydra and Nematostella, representing the lineages Hydrozoa and Anthozoa, respectively. Using pharmacological inhibition in Hydra and a combination of pharmacological and genetic approaches in Nematostella, it was shown in both animals that Notch is required for tentacle morphogenesis and for late stages of stinging cell maturation. Surprisingly, a role for Notch in neural development, which is well documented in bilaterians, was evident in embryonic Nematostella but not in adult Hydra. Adult neurogenesis in the latter seemed to be unaffected by DAPT, a drug that inhibits Notch signaling. To address this apparent discrepancy, we studied the role of Notch in Hydractinia echinata, an additional hydrozoan, in all life stages. Using CRISPR-Cas9 mediated mutagenesis, transgenesis, and pharmacological interference we show that Notch is dispensable for Hydractinia normal neurogenesis in all life stages but is required for the maturation of stinging cells and for tentacle morphogenesis. Our results are consistent with a conserved role for Notch in morphogenesis and nematogenesis across Cnidaria, and a lineage-specific loss of Notch dependence in neurogenesis in hydrozoans.


Assuntos
Extremidades/embriologia , Hidrozoários/embriologia , Neurogênese/fisiologia , Receptores Notch/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Diaminas/farmacologia , Feminino , Hidrozoários/genética , Hibridização In Situ , Masculino , Mutagênese/genética , Neurogênese/genética , Receptores Notch/antagonistas & inibidores , Receptores Notch/genética , Transdução de Sinais/genética , Tiazóis/farmacologia
17.
Cell Rep ; 18(6): 1395-1409, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28178518

RESUMO

SoxB transcription factors and histone deacetylases (HDACs) are each major players in the regulation of neurogenesis, but a functional link between them has not been previously demonstrated. Here, we show that SoxB2 and Hdac2 act together to regulate neurogenesis in the cnidarian Hydractinia echinata during tissue homeostasis and head regeneration. We find that misexpression of SoxB genes modifies the number of neural cells in all life stages and interferes with head regeneration. Hdac2 was co-expressed with SoxB2, and its downregulation phenocopied SoxB2 knockdown. We also show that SoxB2 and Hdac2 promote each other's transcript levels, but Hdac2 counteracts this amplification cycle by deacetylating and destabilizing SoxB2 protein. Finally, we present evidence for conservation of these interactions in human neural progenitors. We hypothesize that crosstalk between SoxB transcription factors and Hdac2 is an ancient feature of metazoan neurogenesis and functions to stabilize the correct levels of these multifunctional proteins.


Assuntos
Cnidários/metabolismo , Cnidários/fisiologia , Histona Desacetilase 2/metabolismo , Neurogênese/fisiologia , Fatores de Transcrição SOXB2/metabolismo , Animais , Evolução Biológica , Regulação para Baixo/fisiologia , Humanos , Neurônios/metabolismo , Neurônios/fisiologia , Regeneração/fisiologia , Células-Tronco/metabolismo , Células-Tronco/fisiologia
18.
Epigenetics Chromatin ; 9(1): 36, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27602058

RESUMO

BACKGROUND: Cnidarians are a group of early branching animals including corals, jellyfish and hydroids that are renowned for their high regenerative ability, growth plasticity and longevity. Because cnidarian genomes are conventional in terms of protein-coding genes, their remarkable features are likely a consequence of epigenetic regulation. To facilitate epigenetics research in cnidarians, we analysed the histone complement of the cnidarian model organism Hydractinia echinata using phylogenomics, proteomics, transcriptomics and mRNA in situ hybridisations. RESULTS: We find that the Hydractinia genome encodes 19 histones and analyse their spatial expression patterns, genomic loci and replication-dependency. Alongside core and other replication-independent histone variants, we find several histone replication-dependent variants, including a rare replication-dependent H3.3, a female germ cell-specific H2A.X and an unusual set of five H2B variants, four of which are male germ cell-specific. We further confirm the absence of protamines in Hydractinia. CONCLUSIONS: Since no protamines are found in hydroids, we suggest that the novel H2B variants are pivotal for sperm DNA packaging in this class of Cnidaria. This study adds to the limited number of full histone gene complements available in animals and sets a comprehensive framework for future studies on the role of histones and their post-translational modifications in cnidarian epigenetics. Finally, it provides insight into the evolution of spermatogenesis.

19.
Curr Opin Genet Dev ; 40: 65-73, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27379898

RESUMO

Hydractinia species have been animal models in developmental biology and comparative immunology for over a century, but are having a renaissance due to the establishment of modern genetic and genomic tools by the growing community of researchers utilizing them. Hydractinia has a predictable and accessible life cycle and its stem cell system, known as interstitial- or i-cells has been a paradigm for animal stem cells since the late 1800s. In adult Hydractinia, i-cells continuously provide progenitors to sustain clonal growth, tissue homeostasis, sexual reproduction and regeneration. We review recent developments in stem cell and regeneration research centered on this animal. Hydractinia joins an established team of cnidarian genetic models in times of rapid progress in these disciplines. While each animal is particularly suited to specific experimental settings, jointly they can provide an integrative insight into the diversity of animal stem cell systems, how they drive regeneration, and how they evolved.


Assuntos
Hidrozoários/genética , Regeneração/genética , Reprodução/genética , Células-Tronco , Animais , Homeostase , Hidrozoários/crescimento & desenvolvimento
20.
Elife ; 4: e05506, 2015 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-25884246

RESUMO

Cnidarians possess remarkable powers of regeneration, but the cellular and molecular mechanisms underlying this capability are unclear. Studying the hydrozoan Hydractinia echinata we show that a burst of stem cell proliferation occurs following decapitation, forming a blastema at the oral pole within 24 hr. This process is necessary for head regeneration. Knocking down Piwi1, Vasa, Pl10 or Ncol1 expressed by blastema cells inhibited regeneration but not blastema formation. EdU pulse-chase experiments and in vivo tracking of individual transgenic Piwi1(+) stem cells showed that the cellular source for blastema formation is migration of stem cells from a remote area. Surprisingly, no blastema developed at the aboral pole after stolon removal. Instead, polyps transformed into stolons and then budded polyps. Hence, distinct mechanisms act to regenerate different body parts in Hydractinia. This model, where stem cell behavior can be monitored in vivo at single cell resolution, offers new insights for regenerative biology.


Assuntos
Cnidários/metabolismo , Regeneração/genética , Células-Tronco/metabolismo , Animais , Proteínas Argonautas/antagonistas & inibidores , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Proliferação de Células , Rastreamento de Células , Cnidários/citologia , RNA Helicases DEAD-box/antagonistas & inibidores , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , DNA-Citosina Metilases/antagonistas & inibidores , DNA-Citosina Metilases/genética , DNA-Citosina Metilases/metabolismo , Decapitação/reabilitação , Regulação da Expressão Gênica , Especificidade de Órgãos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de Célula Única , Células-Tronco/citologia
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