Person:
Fu, Hongxia

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Fu

First Name

Hongxia

Name

Fu, Hongxia

Filters

2015 - 20172

Settings

Author's Publications: search.filters.isAuthorOfPublication.f3384814-4943-4051-a09b-5ab10ba5dbf1

Search Results

Now showing 1 - 2 of 2
  • Thumbnail Image
    Publication
    Flow-induced elongation of von Willebrand factor precedes tension-dependent activation
    (Nature Publishing Group UK, 2017) Fu, Hongxia; Jiang, Yan; Yang, Darren; Scheiflinger, Friedrich; Wong, Wesley; Springer, Timothy
    Von Willebrand factor, an ultralarge concatemeric blood protein, must bind to platelet GPIbα during bleeding to mediate hemostasis, but not in the normal circulation to avoid thrombosis. Von Willebrand factor is proposed to be mechanically activated by flow, but the mechanism remains unclear. Using microfluidics with single-molecule imaging, we simultaneously monitored reversible Von Willebrand factor extension and binding to GPIbα under flow. We show that Von Willebrand factor is activated through a two-step conformational transition: first, elongation from compact to linear form, and subsequently, a tension-dependent local transition to a state with high affinity for GPIbα. High-affinity sites develop only in upstream regions of VWF where tension exceeds ~21 pN and depend upon electrostatic interactions. Re-compaction of Von Willebrand factor is accelerated by intramolecular interactions and increases GPIbα dissociation rate. This mechanism enables VWF to be locally activated by hydrodynamic force in hemorrhage and rapidly deactivated downstream, providing a paradigm for hierarchical mechano-regulation of receptor–ligand binding.
  • Thumbnail Image
    Publication
    Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids
    (Nature Pub. Group, 2015) Freedman, Benjamin S.; Brooks, Craig R.; Lam, Albert; Fu, Hongxia; Morizane, Ryuji; Agrawal, Vishesh; Saad, Abdelaziz F.; Li, Michelle; Hughes, Michael R.; Werff, Ryan Vander; Peters, Derek T.; Lu, Junjie; Baccei, Anna; Siedlecki, Andrew; Valerius, M. Todd; Musunuru, Kiran; McNagny, Kelly M.; Steinman, Theodore; Zhou, Jing; Lerou, Paul; Bonventre, Joseph
    Human-pluripotent-stem-cell-derived kidney cells (hPSC-KCs) have important potential for disease modelling and regeneration. Whether the hPSC-KCs can reconstitute tissue-specific phenotypes is currently unknown. Here we show that hPSC-KCs self-organize into kidney organoids that functionally recapitulate tissue-specific epithelial physiology, including disease phenotypes after genome editing. In three-dimensional cultures, epiblast-stage hPSCs form spheroids surrounding hollow, amniotic-like cavities. GSK3β inhibition differentiates spheroids into segmented, nephron-like kidney organoids containing cell populations with characteristics of proximal tubules, podocytes and endothelium. Tubules accumulate dextran and methotrexate transport cargoes, and express kidney injury molecule-1 after nephrotoxic chemical injury. CRISPR/Cas9 knockout of podocalyxin causes junctional organization defects in podocyte-like cells. Knockout of the polycystic kidney disease genes PKD1 or PKD2 induces cyst formation from kidney tubules. All of these functional phenotypes are distinct from effects in epiblast spheroids, indicating that they are tissue specific. Our findings establish a reproducible, versatile three-dimensional framework for human epithelial disease modelling and regenerative medicine applications.