Улога локалне нише епидермалних матичних ћелија у настанку и развоју хроничних венских улкуса
The role of epidermal stem cells niche in pathogenesis of chronic venous ulcers
Докторанд
Stojadinović, OliveraМентор
Tomić-Canić, MarjanaЧланови комисије
Arsenijević, NebojšaVojvodić, Danilo
Radosavljević, Gordana
Milovanović, Marija
Метаподаци
Приказ свих података о дисертацијиСажетак
Epidermis kože čoveka je višeslojni pločasti keratinizovan epitel koji se
neprekidno obnavlja od strane epidermalnih matičnih ćelija. Ove ćelije se nalaze u
bazalnom sloju kože i folikulu dlake i neprekidno obezbeđuju održavanje homeostaze
kože. Epidermalne matične ćelije takođe učestvuju i u zarastanju rana. Poznato je da su
kod pacijenata koji boluju od hroničnih venskih ulcera, keratinociti na obodima
navedenih promena izmenjeni i nisu u mogućnosti da obezbede normalno zarastanje rana.
Ovaj rad predstavlja prospektivnu kliničku studiju koja je obuhvatila 11 pacijenata sa
hroničnim venskim ulceracijama u okviru koje je, analizom transkripcionih profila
na uzorcima humanog tkiva, pokazano da postoje promene u ekspresiji specifičnih gena
(GATA3, BMPR1, ID2, ID4, LRIG1 i K15) koji regulišu održavanje matičnih ćelija i
njihovu diferencijaciju. Smanjena ekspresija ovih gena ukazuje na osiromašenu
populaciju epidermalnih matičnih ćelija.
Gubitak epidermalnih matičnih ćelija u n...eposrednoj blizini oboda rane ima
za posledicu aktivaciju gena koji stimulišu visoku proliferaciju keratinocita,
smanjen potencijal za njihovu migraciju i nemogućnost zarastanja rana.
Ključne reči: hronični venski ulkusi; epidermalne matične ćelije; mikročip tehnika
The skin is the largest organ of human body and is constantly renewing. Epidermal
and hair follicle stem cells (ESC) reside in distinct niches are indispensable to skin homeostasis
and wound closure. The non-healing edges of venous ulcers (VUs) are healing-incompetent,
consisting of hyper-proliferative and non-migratory keratinocytes implicating possible deregulation of ESCs. The genes regulating ESC niches have been studied primarily in mouse models.
We employed transcriptional profiling of tissue skin specimens derived from the non-healing
edges of VUs, to identify changes in gene expression leading to deregulation of ESCs and their
fate in a prospective clinical study of 11 patients. We discoeverd and confirmed the suppression
of the following genes: bone morphogenetic protein receptor 1 (BMPR1) and GATA binding
protein 3 (GATA3) and inhibitors of DNA-binding proteins 2 and 4 (ID2 and ID4). In addition,
we found down-regulation of leucine-rich repeats and immunoglobulin-lik...e domains protein 1
(LRGIG1), a gene important for maintaining ESCs in a quiescent state, and absence of keratin
15 (K15), a marker of the basal stem cell compartment. These data indicated local depletion of
ESCs. We also found diminished levels of phosphorylated glycogen synthase kinase 3 (GSK3),
nuclear ß-catenin present in keratinocytes and overexpression of its transcriptional target, cmyc, supporting the notion of the activation of the Wnt pathway.
We conclude that loss of genes important for regulation of ESCs and their fate along
with nuclear presence of ß-catenin and c-myc in the VU may lead to the deprivation of local
population of ESC and contribute to a hyper-proliferative, non-migratory wound edge and overall impairment of healing.