Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment

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Abstract

Cell-intrinsic checkpoints limit the proliferative capacity of primary cells in response to telomere dysfunction. It is not known, however, whether telomere dysfunction contributes to cell-extrinsic alterations that impair stem cell function and organ homeostasis. Here we show that telomere dysfunction provokes defects of the hematopoietic environment that impair B lymphopoiesis but increase myeloid proliferation in aging telomerase knockout (Terc−/−) mice. Moreover, the dysfunctional environment limited the engraftment of transplanted wild-type hematopoietic stem cells (HSCs). Dysfunction of the hematopoietic environment was age dependent and correlated with progressive telomere shortening in bone marrow stromal cells. Telomere dysfunction impaired mesenchymal progenitor cell function, reduced the capacity of bone marrow stromal cells to maintain functional HSCs, and increased the expression of various cytokines, including granulocyte colony-stimulating factor (G-CSF), in the plasma of aging mice. Administration of G-CSF to wild-type mice mimicked some of the defects seen in aging Terc−/− mice, including impairment of B lymphopoiesis and HSC engraftment. Conversely, inhibition of G-CSF improved HSC engraftment in aged Terc−/− mice. Taken together, these results show that telomere dysfunction induces alterations of the environment that can have implications for organismal aging and cell transplantation therapies.

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Figure 1: Impaired B-cell development and increased myeloid proliferation of wild-type donor-derived bone marrow cells in telomere-dysfunctional mice.
Figure 2: The bone marrow environment affects hematopoiesis and HSC engraftment.
Figure 3: Telomere dysfunction impairs the function of bone marrow stromal cells in aged Terc−/− mice.
Figure 4: G-CSF impairs HSC function and engraftment in aged Terc−/− mice.

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Acknowledgements

We thank M. Ballmaier for helping with the sorting, and H. Ema and Z. Li for advice and discussion. This work was supported by the Deutsche Forschungsgemeinschaft (Heisenberg Professorship to K.L.R.: Ru 745/8-1, Ru 745 4-1 and KFO119), the Deutsche Krebshilfe e.V. (10-2236-Ru 2), the Roggenbuck-Stiftung, the Wilhelm-Sander-Stiftung and the Fritz-Thyssen Stiftung.

Author information

Z.J. conducted most of the experiments; H.J., M.J., A.G. and A.T. contributed to the in vitro studies; C.R. and C.K. contributed to the B-cell analysis; Z.J. and K.L.R. designed the study and wrote the manuscript; K.L.R. supervised the project.

Correspondence to K Lenhard Rudolph.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Environmental defects in Terc−/− mice impair B-lymphopoiesis. (PDF 104 kb)

Supplementary Fig. 2

Environmental defects in Terc−/− mice accelerate myelopoiesis. (PDF 76 kb)

Supplementary Fig. 3

Environmental defects in Terc−/− mice induce increased mobilization and cell proliferation in hematopoietic stem and progenitor cells. (PDF 45 kb)

Supplementary Table 1

Altered cytokine profile in aged Terc−/− mice. (PDF 19 kb)

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Ju, Z., Jiang, H., Jaworski, M. et al. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med 13, 742–747 (2007) doi:10.1038/nm1578

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