# Measuring and modeling the dynamics of patterning in human stem cells

> **NIH NIH R01** · HARVARD UNIVERSITY · 2024 · $200,570

## Abstract

Project Summary
Important Problem. A critical event in human embryonic development is the elongation of the anterior-posterior
axis. How the embryo achieves stable and sustained axial elongation remains unknown. Progenitor cells in the
tailbud of the elongating embryo contribute to the future spinal cord and musculoskeletal system (1-4). How
underlying gene regulatory networks and morphogen signals drive the fate decisions of these cells between self-
renewal and differentiation in humans still needs to be determined. Addressing these questions will allow us to
understand human axial elongation and the etiology of related diseases (5-11). We address two questions: How
do morphogen signals break anterior-posterior symmetry and drive stable and self-sustained elongation along a
single axis? And, how do the progenitors in the tail bud of the elongating embryo maintain a self-renewing pool
even as they differentiate into neural and mesodermal fates?
Proposed Research: To address these questions, we bring together a robust and validated in vitro organoid
system, live imaging, validated pluripotent stem cell lines with multiple fluorescent reporters, and perturbation
experiments. In Aim 1, we will determine 1A. the cell types and the spatiotemporal expression profiles of
signaling ligands and receptors along the axially elongating organoids; 1B. the signaling pathways necessary for
A-P symmetry breaking, driving cellular rearrangements, growth, and elongation; 1C. the endogenous
spatiotemporal dynamics of these signaling pathways during axial elongation; 1D. the mechanisms for robustly
breaking symmetry and activating self-sustaining elongation only at the posterior pole without being driven by
noise to produce multiple tailbuds and branched axes. In Aim 2, we will determine 2A. The sequence of lineage
decisions that tailbud progenitors make; 2B. The transcription factors (TFs) that control the fate decisions of
these progenitors; 2C. the key signals are required to choose between the maintenance of progenitors and their
differentiation into neural or mesodermal fates; and 2D. Mechanisms by which the signals and TFs maintain a
pool of undifferentiated tailbud progenitors to allow continued elongation.
Impact: Our work will uncover the dynamical system that governs human axial elongation and the fate decisions
of tailbud progenitors. In doing so, it will find the feedback loops and concomitant bistable systems that lead to
self-sustaining elongation, noise suppression mechanisms to prevent axis branching, which otherwise would
lead to a multiple and branched axes, the mechanism that maintains a niche of tailbud progenitors that is
essential for continued elongation, even while allowing these progenitors to differentiate into the developing
tissues. We will thus achieve a quantitative understanding of human axial elongation and determine how the
niche of tailbud progenitors is maintained. The research will reveal fundamental principles governing human
de...

## Key facts

- **NIH application ID:** 11099211
- **Project number:** 3R01GM131105-06S1
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Sharad Ramanathan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $200,570
- **Award type:** 3
- **Project period:** 2019-01-11 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11099211

## Citation

> US National Institutes of Health, RePORTER application 11099211, Measuring and modeling the dynamics of patterning in human stem cells (3R01GM131105-06S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11099211. Licensed CC0.

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