# Molecular architecture of the human knee joint and pelvis at single cell resolution

> **NIH NIH R01** · HARVARD UNIVERSITY · 2024 · $111,145

## Abstract

Project Summary/Abstract
At the cornerstone of human bipedal locomotion are the pelvis and knee, two hind limb skeletal structures for
which we know little about their respective development in humans. Indeed, these structures have complex 3-D
morphologies whose initial patterns arise during the chondrogenic anlagen stage, when coordinated cellular
differentiation and proliferation establish various tissue types and the spatial relationships between different
structural components (e.g., between the knee’s distal femoral condyles and proximal tibial platform, or between
the pelvis’ ilium, pubis, ischium, and acetabular subdomains). Yet, for developing human skeletal structures, we
understand little about these cellular events and their relationships to tissue morphology and function. Moreover,
while one can envision that these events are mediated by a pleiotropic or common ‘skeletal growth’ gene set
and accompanied regulatory apparatus, how this tool kit is used in developing humans to build each structure,
remains a mystery. As biomedicine move towards regenerative therapies for joint tissues and mechanistic
investigations into developmental disorders of the skeleton, it is crucially important to gain a better understanding
of how cells of the skeleton and joints acquire their functional roles, and it is both timely and critical to establish
this at single cell and spatial resolutions. To date, large functional genomics-based consortia, such as an
ENCODE or the ROADMAP EPIGENOMICS PROJECT, have not focused on the skeleton due to logistical
issues in extracting cartilage cells from developing skeletal elements composed of hard extracellular matrix.
However, recent advances on this front by the grant investigators have allowed them to isolate and study
individual cartilage cells from developing human skeletons. The focus of this proposal, therefore, is to more
deeply investigate how the human knee, pelvis, and hind limb in general form in utero, at the level of individual
cells and in understanding how changes in their biology and behavior drive the respective development of each
hind limb structure. This will be accomplished via two main aims, one focused on the use of spatial
transcriptomics to examine expression dynamics histologically (Aim 1), and another on the use of a single cell
(sc) multiomics approach (Aim 2), consisting of scRNA-sequencing (to detect genes) and scATAC-sequencing
(to detect regulatory regions) on the same cell. By simultaneously profiling gene expression and regulatory
element availability at the individual cell level from many cells of these developing human structures, and
spatially, the necessary resolution will be achieved to define small but important nuances in the genetic programs
that govern anatomical-site-specific cartilage cell biology and how it links to hind limb morphology. Use of these
protocols developed by the grant’s Team will help ensure that an extraordinary resource is provided to the
musculoskeletal...

## Key facts

- **NIH application ID:** 11075522
- **Project number:** 3R01AR081274-02S1
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Terence D Capellini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $111,145
- **Award type:** 3
- **Project period:** 2024-09-20 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11075522

## Citation

> US National Institutes of Health, RePORTER application 11075522, Molecular architecture of the human knee joint and pelvis at single cell resolution (3R01AR081274-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11075522. Licensed CC0.

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