Page 11 - ebook

Sirt1 deletion in the non-hematopoietic perivascular niche
is not required for hematopoietic stem cell function in the mice

1
Suyeon Woo , Jayoung Kim , Hee Seon Choi , Munju Kwon and Dongjun Lee 1
1
1
1
1 Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, South Korea
Abstract Results Sirt1 deletion is dispensable for
maintaining hematopoietic stem and
The histone deacetylase SIRT1 regulates a Resveratrol modulates the pools of progenitor cells.
number of cellular responses including 0.3 0.04HSPCs 0.06 0.20 1 .0 0 .8 + /+ Δ /Δ n .s . n .s . 1.0 +/+ Δ/Δ n.s. n.s.
0.8
cell proliferation, apoptosis, and ** 0.03 ** ** 0.15 ** Percent BM 0 .6 n .s . Number of Cells per Limbs (10 5 ) 0.6 n.s.
inflammatory responses via protein % LSK in BM 0.2 % LT-HSC in BM 0.02 % ST-HSC in BM 0.04 % MPP in BM 0.10 0 .4 0 .2 n .s . n .s . n .s . 0.4 n.s. n.s. n.s.
0.2
deacetylation. 0.1 0.01 0.02 0.05 0 .0 H S C L S K C M P G M P M E P C L P 0.0 HSC LSK CMP GMP MEP CLP
0.00
0.00
0.00
0.0
Also, SIRT1 has been implicated in stem Vehicle: Ct Res Vehicle: Ct Res Vehicle: Ct Res Vehicle: Ct Res
cell homeostasis. No differences in hematopoietic stem and
The frequencies of Lin-Sca1+ckit+ cells(LSK), progenitor cells, LSK cells, CMP, GMP, MEP
We show that Sirt1 deletion in non- LT-HSCs (Lin Sca1 cKit CD150 Cd48 ), ST- and CLPs were observed in the Sirt1 △/△ mice
-
+
+
+
-
hematopoietic perivascular bone marrow HSCs (Lin Sca1 cKit CD150 CD48 ), MPP (Lin - compared to control mice.
+
-
+
-
-
niche does not perturb HSC function under Sca1 cKit CD48 ) cells after Resveratrol
+
+
+
the stress of transplantation. treatment (n=5) are significantly decreased. HSCs were preserved in Sirt1 △/△ mice
Therefore, SIRT1 plays a dispensable role under transplantation stress.
in the HSC function in the bone marrow No changes in white blood cells,
niche, but not in the hematopoietic
CD45.2
compartment. . hemoglobin, and platelets counts of BM cells
Sirt1 △/△ mice. WT (+/+)
4
15 n.s. 20 n.s. 2000 n.s. months
1500
15
CD45.2
Introduction 10 6 /ml 10 5 n.s. n.s. HGB (g/dl) 10 PLT (10 6 /ml) 1000 BM cells CD45.2 Sirt1 KO PB and
BM
Δ/Δ
0 n.s. +/+ 5 +/+ 500 +/+ analysi
s
Δ/Δ
WBC LY NEU MO 0 Δ/Δ 0
Sirt1 deletion in the BM niche demonstrated 100 n.s. 100 n.s. n.s.
no differences in WBCs, lymphocytes, and % CD45.2 PB % CD45.2 BM
platelets. 3 50 0 +/+ 50 0 n.s. n.s. +/+
Relative Sirt1 mRNA level 2 1 * There was no significantly differences in PB
Δ/Δ
Δ/Δ
Δ/Δ Myelo
Δ/Δ CD3
+/+ Myelo
+/+ CD3
Δ/Δ B220
+/+ B220
Δ/Δ BM
+/+ BM
+/+
chimerism, BM chimerism, and mature
Δ/Δ
0
hematopoietic cell types between control and
The Sirt1 level was reduced in the CD31 - Sirt1 △/△ mice until 4 months post-
CD45 Ter119 BM cells of Sirt1 △/ △ mice. transplantation.
-
-
Stem cell niches are local tissue
microenvironments that maintain stem △/△
cells and regulate their function by Sirt1 deletion is dispensable for Sirt1 mice did not respond differently
producing factors that act directly on maintaining mature hematopoietic to the stress induced by 5-FU.
stem cells. lineage cells.
8 0 n . s . 8 0 6 0 n . s . 100 +/+ (n=12)
Percent PB 6 0 4 0 2 0 n . s . n . s . Percent BM 4 0 2 0 n . s . n . s . % of survival 75 50 25 Δ /Δ (n =9) n.s.
5-FU
Δ /Δ
M y e lo B 2 2 0 C D 3 M y e lo B 2 2 0 C D 3 Days
Δ /Δ
0 + / + 0 + / + injections: 0 0 7 14 21 28
The Sirt1 △/ △ mice did not showed Under stress condition, exposure of Sirt1 △/ △
differences compared to wild-type mice in mice to serial proliferative stress, such as 5-
their ability to mature cell output in the FU, resulted in no difference survival in
peripheral blood and bone marrow. comparison to control. Thus, Sirt1 deletion in
the BM niche does not perturb HSC function
under stress condition.
Conclusion
✓ Sirt1 deletion in the hematopoietic stem and progenitor system promotes hematopoietic stem and progenitor cells expansion under
stress conditions.
✓ Sirt1 deletion in BM niche such as perivascular cells does not alter HSC function under stress.
✓ Therefore, Sirt1 functions autonomously in stem cells but not in perivascular niche.
부산대학교 GRAND
융합의과학 교육연구단