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지방 유래 중간엽 줄기세포 노화 과정에서 SPHK1의 역할 규명

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Abstract
We have identified a mechanism to diminish the proliferation capacity of cells during cell expansion by using human adipose-derived stromal cells (hAD-SCs) as a model of replicative senescence. hAD-SCs of high passage numbers exhibited a reduced proliferation capacity with accelerated cellular senescence. The levels of key bioactive sphingolipids were significantly increased in these senescent hAD-SCs. Notably, transcription of sphingosine kinase 1 (SPHK1) was down-regulated in hAD-SCs at high passage numbers. SPHK1 knockdown as well as inhibition of its enzymatic activity impeded proliferation of hAD-SCs, with concomitant induction of cellular senescence and accumulation of sphingolipids as in high passage cells. SPHK1 knockdown-accelerated cellular senescence was attenuated by co-treatment of sphingosine-1-phosphate and an inhibitor of ceramide synthesis, fumonisin B1 but not by treatment of either one. Recent research has been uncovered the relationship between SPHK1 and mitochondrial dysfunction. We have shown that mitochondrial ROS, oxygen consumption rate (OCR), and NAD+/NADH ratio were powerfully increased, and the metabolic change for gaining energy is biased against glycolysis in knockdown of SPHK1. And we have concluded that the autophagy nucleation step doesn’t progress well through ATG5-12 conjugated form was decreased in shSPHK1 cells. Taken together, these results suggest that down-regulated transcription of SPHK1 is a critical inducer of altered sphingolipid profiles and enhancing dysfunctional mitochondria and replicative senescence during multiple rounds of cell division.

Keywords: Sphingolipid, Sphingosine kinase 1, SPHK1 transcription, Replicative senescence, Mitochondrial dysfunction, Autophagy, Human adipose-derived stromal cell.
Author(s)
김민경
Issued Date
2021
Awarded Date
2021-02
Type
Dissertation
URI
https://oak.ulsan.ac.kr/handle/2021.oak/5831
http://ulsan.dcollection.net/common/orgView/200000367980
Alternative Author(s)
Min Kyung Kim
Affiliation
울산대학교
Department
일반대학원 의학과
Advisor
김승후
Degree
Doctor
Publisher
울산대학교 일반대학원 의학과
Language
eng
Rights
울산대학교 논문은 저작권에 의해 보호받습니다.
Appears in Collections:
Medicine > 2. Theses (Ph.D)
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