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Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells

Nature Cell Biology volume 12, pages 1046–1056 (2010)Cite this article

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Abstract

Endothelial cells establish an instructive vascular niche that reconstitutes haematopoietic stem and progenitor cells (HSPCs) through release of specific paracrine growth factors, known as angiocrine factors. However, the mechanism by which endothelial cells balance the rate of proliferation and lineage-specific differentiation of HSPCs is unknown. Here, we demonstrate that Akt activation in endothelial cells, through recruitment of mTOR, but not the FoxO pathway, upregulates specific angiocrine factors that support expansion of CD34−Flt3− KLS HSPCs with long-term haematopoietic stem cell (LT-HSC) repopulation capacity. Conversely, co-activation of Akt-stimulated endothelial cells with p42/44 MAPK shifts the balance towards maintenance and differentiation of the HSPCs. Selective activation of Akt1 in the endothelial cells of adult mice increased the number of colony forming units in the spleen and CD34−Flt3− KLS HSPCs with LT-HSC activity in the bone marrow, accelerating haematopoietic recovery. Therefore, the activation state of endothelial cells modulates reconstitution of HSPCs through the modulation of angiocrine factors, with Akt–mTOR-activated endothelial cells supporting the self-renewal of LT-HSCs and expansion of HSPCs, whereas MAPK co-activation favours maintenance and lineage-specific differentiation of HSPCs.

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Figure 1: Establishment of Akt- or MAPK-activated PECs.
Figure 2: Akt-activated PECs are more efficient than MAPK-activated PECs in expanding HSPCs.
Figure 3: HSPC expansion on PECs requires direct cellular interaction.
Figure 4: Activation state of the PECs determines the expression pattern of HSPC-active genes.
Figure 5: Activation of Akt-mTOR pathway in endothelial cells promotes expansion of HSPCs.
Figure 6: Endothelial-specific expression of constitutively active Akt1 (myrAkt) in the adult mice augments HSPC generation and accelerates haematopoiesis.
Figure 7: Akt-activated endothelial cells support expansion of short- and long-term repopulating HSCs in adult mice.

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Acknowledgements

S.R. is supported by Howard Hughes Medical Institute; Ansary Stem Cell Institute; National Institute of Health grants HL097797, U01 HL66592-03, RC1 AI080309; Qatar National Priorities Research Program; Anbinder and Newmans Own Foundations; Empire State Stem Cell Board and the New York State Department of Health grant NYS C024180. We thank G. Lam (Weill Cornell Medical College) for HUVEC culture.

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Author notes

  1. Hideki Kobayashi and Jason M. Butler: Both authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetic Medicine, Howard Hughes Medical Institute, Ansary Stem cell Institute, Weill Cornell Medical College, New York, 10065, NY, USA

    Hideki Kobayashi, Jason M. Butler, Mariko Kobayashi, Bi-Sen Ding, Bryant Bonner, Vi K. Chiu, Daniel J. Nolan, Koji Shido & Shahin Rafii

  2. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, MA, USA

    Rebekah O'Donnell & Laura Benjamin

  3. Shahin Rafii MD Weill Cornell Medical College, HHMI 1300 York Avenue, Room A-863, New York, 10065, NY, USA

    Shahin Rafii

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Contributions

S.R. designed the project. H.K., J.M.B. and S.R. designed experiments and wrote the paper. H.K. and J.M.B. performed most of the data collection and data analysis. M.K. and B.B. performed a significant amount of the experimental work. R.D. and L.B. generated and provided myrAkt1 mouse. B.D., D.N., V.C. and K.S. analysed microarray data and provided advice. The work was carried out in the laboratory of S.R.

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Correspondence to Shahin Rafii.

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Kobayashi, H., Butler, J., O'Donnell, R. et al. Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat Cell Biol 12, 1046–1056 (2010). https://doi.org/10.1038/ncb2108

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