TY - JOUR
T1 - Bone marrow skeletal stem/progenitor cell defects in dyskeratosis congenita and telomere biology disorders
AU - Balakumaran, Arun
AU - Mishra, Prasun J.
AU - Pawelczyk, Edyta
AU - Yoshizawa, Sayuri
AU - Sworder, Brian J.
AU - Cherman, Natasha
AU - Kuznetsov, Sergei A.
AU - Bianco, Paolo
AU - Giri, Neelam
AU - Savage, Sharon A.
AU - Merlino, Glenn
AU - Dumitriu, Bogdan
AU - Dunbar, Cynthia E.
AU - Young, Neal S.
AU - Alter, Blanche P.
AU - Robey, Pamela G.
PY - 2015/1/29
Y1 - 2015/1/29
N2 - Dyskeratosis congenita (DC) is an inherited multisystem disorder, characterized by oral leukoplakia, nail dystrophy, andabnormal skin pigmentation, as well as high rates ofbone marrow (BM) failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the BM stromal cell population (BMSCs, also known as BM-derived mesenchymal stem cells), may contribute to the hematologic phenotype. TBD-BMSCs exhibited reduced clonogenicity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by small interfering TERC-RNA (siTERC-RNA) recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony-forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the messenger RNA level and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to BM failure in TBD. (Blood. 2015;125(5):793-802).
AB - Dyskeratosis congenita (DC) is an inherited multisystem disorder, characterized by oral leukoplakia, nail dystrophy, andabnormal skin pigmentation, as well as high rates ofbone marrow (BM) failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the BM stromal cell population (BMSCs, also known as BM-derived mesenchymal stem cells), may contribute to the hematologic phenotype. TBD-BMSCs exhibited reduced clonogenicity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by small interfering TERC-RNA (siTERC-RNA) recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony-forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the messenger RNA level and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to BM failure in TBD. (Blood. 2015;125(5):793-802).
KW - BMSCs from patients with tbds are abnormal and unable to support hematopoiesis
KW - Knockdown of terc with sirna recapitulates the tbd-bmsc phenotype
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U2 - 10.1182/blood-2014-06-566810
DO - 10.1182/blood-2014-06-566810
M3 - Article
C2 - 25499762
AN - SCOPUS:84921927080
SN - 0006-4971
VL - 125
SP - 793
EP - 802
JO - Blood
JF - Blood
IS - 5
ER -