Adipocytes: more than a tissue filler of bone marrow

Wen-yi Lu , Kai-yan Liu*

Peking University Institute of Hematology （ PUIH）Peking University People’s Hospital

Beijing Key Laboratory of HSCTBeijing, P.R.China

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BackgroundDelayed hematopoietic recovery is an intractable problem in patients receiving high-dose chemotherapy or bone marrow transplantation and it seriously affects patient survival.

F

Adipocyte-rich marrow

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Background

Naveiras et al. Nature 2009Zhu et al. Int J Hematol 2013

Snyder et al. Nature 1995 Tripathy et al. Stem Cells Int 2014

Poloni et al. Exp Hematol 2013Spindler et al. Stem Cell Dev 2014

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1. To investigate the role of adipocytes in stress hematopoiesis.

2. To explore the molecular mechanisms involved in the hematopoietic inhibition imposed by fatty marrow.

Objective

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Part-1

PPAR γ agonist rosiglitazone delayed hematopoietic recovery following myelosuppressive stress

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Method

4 weeks

5-Fu

2 weeks

BM/Spleen/PB Cells

CFU assay

Cell phenotype

Normal or Rosiglitazone-enriched diet

Normal or Rosiglitazone-enriched diet

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Part1-Results1. Rosiglitazone delays hematopoietic recovery after 5-Fu treatment

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Part1-Results2. Rosiglitazone treatment maintains LSK while decreases the proportion of GMP after 5-Fu treatment

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Part1-Results

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Part1-Results3. Rosiglitazone has no effect on HSPC at stress condition in vitro

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4. Rosiglitazone-treated stromal cells inhibit myeloid differentiation from HSPC

from HSPC

Part1-Results

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Part1-Conclusions

PPARγ agonist rosiglitazone could inhibit the myeloid

differentiation without compromising HSC function,

which may finally lead to a delayed hematopoietic

recovery.

Rosiglitazone inhibit the myeloid differentiation by

promoting adipogenesis rather than directly affecting

HSPC.

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Part-2

Which molecule mediates the effect of adipocyte on hematopoiesis?

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Part2-Results1. Impact of adipocytic cell on the proliferation and differentiation of mPB HSPC

The effect of adipocytes on the differentiation of mPB-derived CD34+ HSPC in transwell coculture system

CD33+(%) CD19+(%) CD7+(%) CD235a+(%)

MSC group 84.28±3.89 0.43±0.15* 0.33±0.15 0.80±0.20

Adipocyte group 77.76±1.40 0.07±0.06* 0.23±0.15 1.16±0.12

2 、 Adipocyte activates adiponectinR1-AMPK signaling pathway of HSPC

P-A

MPK

MSC group Adipocyte group

P-p3

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Part1-Results3. The effect of adipocytes on HSPC could be partially reversed by anti-adiponectin antibody

CD38

CD

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CD7

CD

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CD38

MSC group Adipocyte group Adipocyte+anti-APN group

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Part2-Conclusions

Adipocyte could impair the proliferation and

differentiation of HSPC.

The process may be mediated by adiponectinR-

AMPK signaling pathway.

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1. Hematopoietic recovery post-chemotherapy is delayed by rosiglitazone induced bone marrow adipogenesis.

2. Adiponectin may mediate the adverse effect of adipocyte on hematopoiesis.

Summary

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Discussion&Plan

Acknowledgements

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Dr. Weimin Wang Yao Zhang Shujuan Wang Yonghuai Feng

Prof. Kaiyan Liu