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Restoration of keratinocytic phenotypes in autonomous trisomy-rescued…
Restoration of keratinocytic phenotypes in
autonomous trisomy-rescued cells
Background
Trisomy 21 can lead to many different dermatological abnormalities
Skin barrier dysfunction are heavily associated with T21, like psoriasis, atopic dermatitis, and infections
few studies have focused on differences in
epidermal characteristics between Down syndrome and
euploid cells in vitro.
Disease-specific iPSCs,
therefore, serve as a powerful tool for investigating the
mechanisms of Down syndrome
differences in genetic backgrounds of individuals
has hindered the assessment the phenotypic disparities between Down syndrome cells and healthy control cells.
In this study, the lifespan of
trisomy-rescued iPSC-derived keratinocytes was extended to more than 34 population doublings over a period of 160 days with
maintenance of keratinocytic phenotypes.
Methods
used patient-derived induced pluripotent stem cells (iPSCs) carrying trisomy 21 (T21) and naturally occurring trisomy-rescued disomy 21 (D21) iPSCs that had spontaneously lost the extra chromosome 21
originated from the same donor
iPSCs were induced to become keratinocytes using an epidermal differentiation protocol involving media and signaling factors that promote ectodermal and epidermal lineage commitment.
Morphological assessment examined by phase-contrast microscopy to identify phenotypic differences between T21 and D21 cells.
Cultured keratinocytes were seeded onto scaffold/support matrices and grown at an air–liquid interface to generate 3D epidermal tissue that closely mimics human skin.
Engineered tissues were sectioned and stained to assess epidermal thickness, layer organization, keratinization, and localization of differentiation markers.
outcomes from T21-derived keratinocytes were directly compared with D21 rescue cells to determine whether correcting chromosome dosage restored normal keratinocyte phenotypes.
Results
Both trisomy 21 (T21) and rescued disomy 21 (D21) iPSCs were differentiated into keratinocyte-like cells, confirming that epidermal lineage commitment was possible in both groups.
Keratinocytes carrying trisomy 21 demonstrated slower expansion and decreased growth potential, suggesting that the extra chromosome negatively affects epidermal stem/progenitor cell function.
D21 keratinocytes displayed more normal morphology, stronger growth, and improved expression of keratinocyte markers, showing that removal of the extra chromosome 21 reversed many defects.
Findings support that many skin-related abnormalities in Down syndrome are directly linked to gene dosage imbalance from the extra chromosome 21 rather than unrelated patient-specific genetics.
The study demonstrates that correcting trisomy at the cellular level can restore normal tissue phenotypes, highlighting the value of isogenic iPSC models for studying Down syndrome mechanisms.