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

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:

URL

Impact factor

Impact factor: 3.517

RIV identification code

RIV/00216224:14110/18:00104194

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.3389/fgene.2018.00345

UT WoS

000443045400001

Keywords in English

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

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.

Citovat

SUSHAMA JOSE, Shyam, Federico TIDU, Petra LÁZNIČKOVÁ, Tomáš KEPÁK, Kamila BENDICKOVA and Jan FRIČ. The Telomerase Complex Directly Controls Hematopoietic Stem Cell Differentiation and Senescence in an Induced Pluripotent Stem Cell Model of Telomeropathy. FRONTIERS IN GENETICS. LAUSANNE: FRONTIERS MEDIA SA, 2018, vol. 9, No 345, p. 1-19. ISSN 1664-8021. Available from: https://dx.doi.org/10.3389/fgene.2018.00345.

@article{1455236,
   author = {Sushama Jose, Shyam and Tidu, Federico and Lázničková, Petra and Kepák, Tomáš and Bendickova, Kamila and Frič, Jan},
   article_location = {LAUSANNE},
   article_number = {345},
   doi = {http://dx.doi.org/10.3389/fgene.2018.00345},
   keywords = {telomerase imbalance; hematopoiesis; immune function; immunosenescence; iPSC; dyskeratosis congenita; myelopoiesis},
   language = {eng},
   issn = {1664-8021},
   journal = {FRONTIERS IN GENETICS},
   title = {The Telomerase Complex Directly Controls Hematopoietic Stem Cell Differentiation and Senescence in an Induced Pluripotent Stem Cell Model of Telomeropathy},
   url = {https://www.frontiersin.org/articles/10.3389/fgene.2018.00345/full},
   volume = {9},
   year = {2018}
}

TY  - JOUR
ID  - 1455236
AU  - Sushama Jose, Shyam - Tidu, Federico - Lázničková, Petra - Kepák, Tomáš - Bendickova, Kamila - Frič, Jan
PY  - 2018
TI  - The Telomerase Complex Directly Controls Hematopoietic Stem Cell Differentiation and Senescence in an Induced Pluripotent Stem Cell Model of Telomeropathy
JF  - FRONTIERS IN GENETICS
VL  - 9
IS  - 345
SP  - 1-19
EP  - 1-19
PB  - FRONTIERS MEDIA SA
SN  - 16648021
KW  - telomerase imbalance
KW  - hematopoiesis
KW  - immune function
KW  - immunosenescence
KW  - iPSC
KW  - dyskeratosis congenita
KW  - myelopoiesis
UR  - https://www.frontiersin.org/articles/10.3389/fgene.2018.00345/full
L2  - https://www.frontiersin.org/articles/10.3389/fgene.2018.00345/full
N2  - 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.
ER  -

SUSHAMA JOSE, Shyam, Federico TIDU, Petra LÁZNIČKOVÁ, Tomáš KEPÁK, Kamila BENDICKOVA and Jan FRIČ. The Telomerase Complex Directly Controls Hematopoietic Stem Cell Differentiation and Senescence in an Induced Pluripotent Stem Cell Model of Telomeropathy. \textit{FRONTIERS IN GENETICS}. LAUSANNE: FRONTIERS MEDIA SA, 2018, vol.~9, No~345, p.~1-19. ISSN~1664-8021. Available from: https://dx.doi.org/10.3389/fgene.2018.00345.

Detailed Information on Publication Record