J 2018

The Telomerase Complex Directly Controls Hematopoietic Stem Cell Differentiation and Senescence in an Induced Pluripotent Stem Cell Model of Telomeropathy

SUSHAMA JOSE, Shyam, Federico TIDU, Petra LÁZNIČKOVÁ, Tomáš KEPÁK, Kamila BENDICKOVA et. al.

Basic information

Original name

The Telomerase Complex Directly Controls Hematopoietic Stem Cell Differentiation and Senescence in an Induced Pluripotent Stem Cell Model of Telomeropathy

Authors

SUSHAMA JOSE, Shyam (356 India, belonging to the institution), Federico TIDU (380 Italy, belonging to the institution), Petra LÁZNIČKOVÁ (203 Czech Republic, belonging to the institution), Tomáš KEPÁK (203 Czech Republic), Kamila BENDICKOVA (203 Czech Republic) and Jan FRIČ (203 Czech Republic, guarantor)

Edition

FRONTIERS IN GENETICS, LAUSANNE, FRONTIERS MEDIA SA, 2018, 1664-8021

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10603 Genetics and heredity

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

Impact factor

Impact factor: 3.517

RIV identification code

RIV/00216224:14110/18:00104194

Organization unit

Faculty of Medicine

DOI

UT WoS

000443045400001

Keywords in English

telomerase imbalance; hematopoiesis; immune function; immunosenescence; iPSC; dyskeratosis congenita; myelopoiesis

Tags

Tags

International impact, Reviewed
Změněno: 10/8/2021 08:47, Mgr. Tereza Miškechová

Abstract

V originále

Telomeropathies are rare disorders associated with impaired telomere length control mechanisms that frequently result from genetic mutations in the telomerase complex. Dyskeratosis congenita is a congenital progressive telomeropathy in which mutation in the telomerase RNA component (TERC) impairs telomere maintenance leading to accelerated cellular senescence and clinical outcomes resembling premature aging. The most severe clinical feature is perturbed hematopoiesis and bone-marrow failure, but the underlying mechanisms are not fully understood. Here, we developed a model of telomerase function imbalance using shRNA to knockdown TERC expression in human induced pluripotent stem cells (iPSCs). We then promoted in vitro hematopoiesis in these cells to analyze the effects of TERC impairment. Reduced TERC expression impaired hematopoietic stem-cell (HSC) differentiation and increased the expression of cellular senescence markers and production of reactive oxygen species. Interestingly, telomere length was unaffected in shTERC knockdown iPSCs, leading to conclusion that the phenotype is controlled by non-telomeric functions of telomerase. We then assessed the effects of TERC-depletion in THP-1 myeloid cells and again observed reduced hematopoietic and myelopoietic differentiative potential. However, these cells exhibited impaired telomerase activity as verified by accelerated telomere shortening. shTERC-depleted iPSC-derived and THP-1-derived myeloid precursors had lower phagocytic capacity and increased ROS production, indicative of senescence. These findings were confirmed using a BIBR1532 TERT inhibitor, suggesting that these phenotypes are dependent on telomerase function but not directly linked to telomere length. These data provide a better understanding of the molecular processes driving the clinical signs of telomeropathies and identify novel roles of the telomerase complex other than regulating telomere length.