Journal article
Dyskeratosis Congenita Dermal Fibroblasts are Defective in Supporting the Clonogenic Growth of Epidermal Keratinocytes
Aging and disease, Vol.3(6), pp.427-437
2012
PMCID: PMC3522509
PMID: 23251848
Abstract
Telomere shortening is associated with cellular senescence and aging. Dyskeratosis congenita (DC) is a premature aging syndrome caused by mutations in genes for telomerase components or telomere proteins. DC patients have very short telomeres and exhibit aging-associated pathologies including epidermal abnormalities and bone marrow failure. Here, we show that DC skin fibroblasts are defective in their ability to support the clonogenic growth of epidermal keratinocytes. Conditioned media transfer experiments demonstrated that this defect was largely due to lack of a factor or factors secreted from the DC fibroblasts. Compared to early passage normal fibroblasts, DC fibroblasts express significantly lower transcript levels of several genes that code for secreted proteins, including Insulin-like Growth Factor 1 (IGF1) and Hepatocyte Growth Factor (HGF). Aged normal fibroblasts with short telomeres also had reduced levels of IGF1 and HGF, similar to early passage DC fibroblasts. Knockdown of IGF1 or HGF in normal fibroblasts caused a reduction in the capacity of conditioned media from these fibroblasts to support keratinocyte clonogenic growth. Surprisingly, reconstitution of telomerase in DC fibroblasts did not significantly increase transcript levels of IGF1 or HGF or substantially increase the ability of the fibroblasts to support keratinocyte growth, indicating that the gene expression defect is not readily reversible. Our results suggest that telomere shortening in dermal fibroblasts leads to reduction in expression of genes such as IGF1 and HGF and that this may cause a defect in supporting normal epidermal proliferation.
Details
- Title: Subtitle
- Dyskeratosis Congenita Dermal Fibroblasts are Defective in Supporting the Clonogenic Growth of Epidermal Keratinocytes
- Creators
- Erin M Buckingham - Department of Microbiology, University of Iowa, Iowa City, IA, USAFrederick D Goldman - Department of Microbiology, University of Iowa, Iowa City, IA, USAAloysius J Klingelhutz - Department of Microbiology, University of Iowa, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Aging and disease, Vol.3(6), pp.427-437
- Publisher
- JKL International LLC
- PMID
- 23251848
- PMCID
- PMC3522509
- ISSN
- 2152-5250
- eISSN
- 2152-5250
- Language
- English
- Date published
- 2012
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Radiation Oncology
- Record Identifier
- 9984002390802771
Metrics
35 Record Views