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Master's Dissertation
DOI
https://doi.org/10.11606/D.41.2022.tde-29112022-161747
Document
Author
Full name
Maria Susana Joya Marodin
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2022
Supervisor
Committee
Okamoto, Oswaldo Keith (President)
Kobayashi, Gerson Shigeru
Lombello, Christiane Bertachini
Vainzof, Mariz
Title in Portuguese
Avaliação do potencial oncogênico e imunomodulador de células estromais mesenquimais com trissomia 5
Keywords in Portuguese
Aneuploidia
Célula estromal mesenquimal
Terapia celular
Trissomia 5
Tumorigênese
Abstract in Portuguese
Células estromais mesenquimais (MSC) podem ser isoladas e expandidas para uso em terapia celular. Durante o processo de expansão, podem surgir alguns clones aneuploides em suas populações, que geralmente são descartadas devido ao receio da aneuploidia poder contribuir com a formação de tumores nos pacientes. Entretanto, estudos que demonstram o potencial tumorigênico de MSC, utilizam células que já sofreram transformação neoplásica durante expansão in vitro. Na realidade clínica, células que demonstram sinais de transformação não são candidatas a infusão no paciente. Sendo assim, é mais relevante para o contexto clínico saber se MSC não transformadas, mas com clones com aneuploidias, incluindo a trissomia 5, poderiam dar origem a tumores nos pacientes e se são capazes de manter sua propriedade terapêutica. Para tanto, o potencial tumorigênico e imunomodulador de MSC com clones da trissomia 5 (MSC-T5) que surgiram espontaneamente durante expansão para uso clínico foi avaliado. Células tumorais, MSC-T5 e MSC euploides tiveram seu crescimento populacional, proliferação e senescência celular avaliados comparativamente. A potência imunomoduladora foi avaliada por expressão gênica em reposta a estimulação com IFNγ e o potencial tumorigênico in vivo foi investigado por injeção subcutânea das células em camundongos Balb c/ NUDE. MSC-T5 não demonstrou potencial oncogênico in vitro, pois apresentaram baixo potencial proliferativo e senescência precoce em relação aos controles, resultando em baixo potencial de expansão. Sua resposta transcricional ao IFNγ é compatível com MSC com potência imunomoduladora e não demonstraram potencial tumorigênico in vivo. Portanto, MSC-T5 são mais seguras e potentes do que previamente imaginado para uso clínico.
Title in English
Evaluation of oncogenic and immunomodulatory potential of mesenchymal stem cells with trisomy 5
Keywords in English
Aneuploidy
Cell therapy
Mesenchymal stromal cell
Trisomy 5
Tumorigenesis
Abstract in English
Mesenchymal stromal cells (MSC) can be harvested and expanded for cell therapy applications. During the expansion process, some aneuploid clones can emerge in MSC populations. These samples are usually discarded due to the risk of tumor development in patients. However, studies that show the tumorigenic potential of MSC use already transformed MSC with chromosomal alterations. In a clinic context, cells with signals of transformation are not allowed to be released into patient. Therefore, the most relevant question in a clinic context is whether non-transformed MSC with clones with cytogenetic alterations, including trisomy 5, would be able to give rise to tumors in the patient and whether they can keep its therapeutics properties. In this context, the tumorigenic and immunomodulatory potential of MSC with trisomy 5 (MSC-T5) that have emerged spontaneously during expansion for clinic use were evaluated. Tumor cells, MSC-T5 and euploid MSC were comparatively evaluated according to its population growth, cell proliferation and cell senescence. The immunomodulatory potential was evaluated by gene expression in response to IFNγ stimulation and the in vivo tumorigenic potential were accessed by cell subcutaneous injection into Balb c/ NUDE mice. MSC-T5 did not show an oncogenic potential in vitro, as it showed a low proliferative potential and early senescence in comparison to euploid MSC and tumor controls, resulting in a low expansion potential. MSC with clones with trisomy 5 showed a transcriptional response to IFNγ, which is compatible with MSC with immunomodulatory potency. In addition, they did not show any in vivo tumorigenic potential. Therefore, MSC with trisomy 5 are safer and more potent for clinical application than previously thought.
 
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MaSusana_Marodin.pdf (2.43 Mbytes)
Publishing Date
2023-03-23
 
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