Down syndrome iPSC model: endothelial perspective on tumor development

Abstract

Trisomy 21 (T21), known as Down syndrome (DS), is a widely studied chromosomal abnormality. Previous studies have shown that DS individuals have a unique cancer profile. While exhibiting low solid tumor prevalence, DS patients are at risk for hematologic cancers, such as acute megakaryocytic leukemia and acute lymphoblastic leukemia. We speculated that endothelial cells are active players in this clinical background. To this end, we hypothesized that impaired DS endothelial development and functionality, impacted by genome-wide T21 alterations, potentially results in a suboptimal endothelial microenvironment with the capability to prevent solid tumor growth. To test this hypothesis, we assessed molecular and phenotypic differences of endothelial cells differentiated from Down syndrome and euploid iPS cells. Microarray, RNA-Seq, and bioinformatic analyses revealed that most significantly expressed genes belong to angiogenic, cytoskeletal rearrangement, extracellular matrix remodeling, and inflammatory pathways. Interestingly, the majority of these genes are not located on Chromosome 21. To substantiate these findings, we carried out functional assays. The obtained phenotypic results correlated with the molecular data and showed that Down syndrome endothelial cells exhibit decreased proliferation, reduced migration, and a weak TNF-α inflammatory response. Based on this data, we provide a set of genes potentially associated with Down syndrome's elevated leukemic incidence and its unfavorable solid tumor microenvironment-highlighting the potential use of these genes as therapeutic targets in translational cancer research.

The Study of Alternative Splicing Events in Human Induced Pluripotent Stem Cells From a Down's Syndrome Patient

“…In addition, abnormal cell adhesion was also found in the bioinformatics analysis of other DS hiPSCs (Hibaoui et al, 2014 ; Gonzales et al, 2018 ). These results are consistent with the other studies, in which the RNA-seq are used as the major research platform (Hibaoui et al, 2014 ; Gonzales et al, 2018 ; Perepitchka et al, 2020 ).…”

Realizing the potential of exploiting human IPSCs and their derivatives in research of Down syndrome

“…They also found that trisomy 21 enhanced the proliferative phenotype, reproducing the cellular and molecular abnormalities in DSassociated AMKL. Galat et al (2020) showed DS iPSC-derived progenitor stromal cells had aberrant musculoskeletal development and resistance to solid tumors. Additionally, Perepitchka et al (2020) found that DS iPSC-derived endothelial cells exhibited decreased proliferation, migration, and inflammatory response.…”

“…Galat et al (2020) showed DS iPSC-derived progenitor stromal cells had aberrant musculoskeletal development and resistance to solid tumors. Additionally, Perepitchka et al (2020) found that DS iPSC-derived endothelial cells exhibited decreased proliferation, migration, and inflammatory response. They also reported a set of genes potentially associated with the unfavorable solid tumor microenvironment and with the elevated leukemia risk in DS, suggesting that these genes could be potential therapeutic targets in translational cancer research (Perepitchka et al, 2020).…”

Leucemia transitória da Síndrome de Down: desafios no diagnóstico e tratamento odontológico

“…Não se sabe ainda o porquê dessa prevalência, apesar de alguns estudos apontarem que as células endoteliais de pacientes com SD poderiam ser a chave para a explicação 10 . Mas é fato a importância de um acompanhamento do paciente desde o seu primeiro dia de vida [11][12][13] .…”