[Paper Review] Topological defect launches 3D mound in the active nematic sheet of neural progenitors

Kyogo Kawaguchi, Ryoichiro Kageyama+1 more|arXiv (Cornell University)|May 20, 2016

Micro and Nano Robotics3 citations

TL;DR

This study reveals that +1/2 topological defects in a 2D active nematic sheet of neural progenitor cells (NPCs) trigger the formation of 3D mounds through local cell accumulation, driven by anisotropic friction and active forces. The mechanism explains how topological defects act as hubs for cell density control in active nematic systems, with experimental validation via live imaging and single-cell tracking showing velocity reversals and phase-dependent dynamics.

ABSTRACT

Cultured stem cells have become a standard platform not only for regenerative medicine and developmental biology but also for biophysical studies. Yet, the characterization of cultured stem cells at the level of morphology and macroscopic patterns resulting from cell-to-cell interactions remain largely qualitative, even though they are the simplest features observed in everyday experiments. Here we report that neural progenitor cells (NPCs), which are multipotent stem cells that give rise to cells in the central nervous system, rapidly glide and stochastically reverse its velocity while locally aligning with neighboring cells, thus showing features of an active nematic system. Within the two-dimensional nematic pattern, we find interspaced topological defects with +1/2 and -1/2 charges. Remarkably, we identified rapid cell accumulation leading to three-dimensional mounds at the +1/2 topological defects. Single-cell level imaging around the defects allowed quantification of the evolving cell density, clarifying that not only cells concentrate at +1/2 defects, but also escape from -1/2 defects. We propose the mechanism of instability around the defects as the interplay between the anisotropic friction and the active force field, thus addressing a novel universal mechanism for local cell density control.

Motivation & Objective

• To understand how collective cell motion and alignment in neural progenitor cell (NPC) cultures give rise to macroscopic patterns.
• To investigate the role of topological defects in organizing 3D morphogenesis in a 2D active nematic system.
• To quantify cell dynamics, including velocity switching and nematic order, and link them to cell cycle phases.
• To identify the physical mechanism underlying local cell accumulation at +1/2 defects and escape from -1/2 defects.
• To establish a biophysical model linking active nematic behavior to emergent 3D structures in stem cell cultures.

Proposed method

• Live widefield imaging of NPCs expressing H2B-mCherry to track single-cell trajectories and quantify motion dynamics.
• Use of Fucci cell cycle reporter to correlate velocity reversal with G1/G2 phases.
• Calculation of nematic order parameter and autocorrelation functions to analyze alignment and memoryless motion.
• Spatial correlation analysis of cell density and alignment fluctuations in defect-free regions to identify extensile active nematic behavior.
• Fitting of nematic order profiles around defects using radially symmetric models to extract defect core structure.
• Simulation of density evolution around defects using parameters derived from experimental fitting to validate theoretical predictions.

Experimental results

Research questions

• RQ1 How do topological defects in a 2D active nematic sheet of NPCs influence 3D morphogenesis?
• RQ2 What physical mechanism drives cell accumulation at +1/2 defects and depletion at -1/2 defects?
• RQ3 How do cell velocity reversals and nematic order correlate with cell cycle phase in NPCs?
• RQ4 To what extent do active nematic correlations and giant number fluctuations emerge in NPC cultures?
• RQ5 Can the observed mound formation be explained by the interplay between anisotropic friction and active force fields?

Key findings

• NPCs exhibit rapid, nematic-like motion with velocity reversals occurring on a timescale of ~3 hours in high-density cultures.
• +1/2 topological defects act as nucleation sites for 3D mounds, with cell density growing radially outward at a rate consistent with theoretical predictions.
• Cells accumulate at +1/2 defects and escape from -1/2 defects, as quantified by single-cell tracking and density profile fitting.
• The nematic autocorrelation function decays slowly, indicating 180° reorientation rather than random motion, consistent with active nematic dynamics.
• Spatial correlations between density and alignment fluctuations are positive in the first and third quadrants, confirming the system as an extensile active nematic.
• Simulations using experimentally derived parameters reproduce the observed mound growth, supporting the proposed mechanism of instability driven by anisotropic friction and active forces.