Induced pluripotent stem (iPS) cells differentiation in hepatocytes, neurons, and blood cells from fibroblasts of patients with telomere diseases

• Grant number: 12/08119-4
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2012
• End date: March 31, 2016
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Rodrigo do Tocantins Calado de Saloma Rodrigues
• Grantee: Flávia Sacilotto Donaires Ramos
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 12/18434-4 - Induced pluripotent stem (IPS) cells differentiation in hepatocytes, neurons, and blood cells from fibroblasts of patients with telomere diseases, BE.EP.DR

Abstract

Telomeres are nucleotide specific sequences at the ends of eukaryotic linear chromosomes and are responsible for protecting chromosome termini. Telomeres shorten with mitotic cell division, but are maintained in stem cells by the action of telomerase that enzymatically adds nucleotides to the 3' of the chromosome. Telomerase is constituted by the reverse transcriptase (TERT), a RNA component (TERC), and associated proteins, including dyskerin, encoded by the DKC1 gene. Mutations in these genes can result in human diseases, including aplastic anemia, pulmonary fibrosis, hepatic cirrhosis and dyskeratosis congenita. The generation of induced pluripotent stem (iPS) cells has been used as a model in some human diseases, as reprogramming to the pluripotent state may maintain the initial genotypic characteristics. In our laboratory, together with the NIH, we successfully generated iPS cells from patients with mutations in TERT, TERC, and DKC1 and we observed telomere elongation deficiency during reprogramming. In this project, we plan to promote the differentiation of iPS cells from patients and healthy individuals in different cell types affected (hematopoietic and hepatocytes) or not (neurons) in telomere diseases aiming (1) to characterize the telomere dynamics and telomerase expression during the differentiation process in telomerase-deficient and healthy iPS cells and (2) to determine if the telomerase deficiency modulates the ability of pluripotent cells to differentiate into blood and hepatocytes, which could contribute to the pathophysiology of the disease.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DONAIRES, FLAVIA S.; ALVES-PAIVA, RAQUEL M.; GUTIERREZ-RODRIGUES, FERNANDA; DA SILVA, FERNANDA BORGES; TELLECHEA, MARIA FLORENCIA; MOREIRA, LILIAN FIGUEIREDO; SANTANA, BARBARA A.; TRAINA, FABIOLA; DUNBAR, CYNTHIA E.; WINKLER, THOMAS; et al. Telomere dynamics and hematopoietic differentiation of human DKC1-mutant induced pluripotent stem cells. STEM CELL RESEARCH, v. 40, OCT 2019. (12/08119-4, 12/18434-4, 13/08135-2)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

RAMOS, Flávia Sacilotto Donaires. Telomere dynamics and hematopoietic differentiation of human DKC1-mutant induced pluripotent stem cells. 2016. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.