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TGF-β-induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche

Takashi Yahata, Abd Aziz Ibrahim, Yukari Muguruma, Mesut Eren, Alexander M. Shaffer, Nobuo Watanabe, Satoko Kaneko, Tetsuo Nakabayashi, Takashi Dan, Noriaki Hirayama, Douglas E. Vaughan, Toshio Miyata and Kiyoshi Ando

Key points

  • TGF-β-induced intracellular PAI-1 regulates the balance of HSPCs localization between bone marrow and periphery.

  • Intracellular PAI-1 inhibits Furin-dependent maturation of MT1-MMP in HSPCs, resulting in the suppression of HSPC motility.

Abstract

Hematopoietic stem and progenitor cells (HSPCs) reside in the supportive stromal niche in bone marrow (BM); when needed, however, they are rapidly mobilized into the circulation, suggesting that HSPCs are intrinsically highly motile but are usually stayed in the niche. We questioned what determines the motility of HSPCs. Here we show that transforming growth factor (TGF)-β-induced intracellular plasminogen activator inhibitor (PAI)-1 activation is responsible for keeping HSPCs in the BM niche. We found that the expression of PAI-1, a downstream target of TGF-β-signaling, was selectively augmented in niche-residing HSPCs. Functional inhibition of the TGF-β−PAI-1 signal increased MT1-MMP-dependent cellular motility, causing a detachment of HSPCs from the TGF-β-expressing niche cells, such as megakaryocytes. Furthermore, consistently high motility in PAI-1-deficient HSPCs was demonstrated by both a trans-well migration assay and reciprocal transplantation experiments, indicating that intracellular, not extracellular, PAI-1 suppresses the motility of HSPCs, thereby causing them to stay in the niche. Mechanistically, intracellular PAI-1 inhibited the proteolytic activity of proprotein convertase Furin, diminishing MT1-MMP activity. This reduced expression of MT1-MMP in turn affected the expression levels of several adhesion/de-adhesion molecules for determination of HSPC localization, such as CD44, VLA-4, and CXCR4, which then promoted the retention of HSPCs in the niche. Our findings open up a new field for the study of intracellular proteolysis as a regulatory mechanism of stem cell fate, which has the potential to improve clinical HSPC mobilization and transplantation protocols.

  • Submitted February 10, 2017.
  • Accepted August 10, 2017.