# Dynamic heterogeneity of nucleus pulposus cells from development to degeneration

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2022 · $176,963

## Abstract

Abstract
 Lumbar intervertebral disc degeneration is a cascade of cellular, structural and mechanical changes that is
strongly implicated as a cause of low back pain. Current therapies for painful disc degeneration, conservative
or surgical, focus only on alleviating symptoms. There is a critical need for new therapies that restore disc
structure and mechanical function by directly addressing the underlying biological causes. A key challenge to
developing effective treatments for disc degeneration is the need to recapitulate the structural complexity and
specialized extracellular matrix (ECM) of the component tissues, which comprise cells of multiple
developmental lineages. The central nucleus pulposus (NP) is implicated in the initiation of disc degeneration.
The developmental origin of NP cells was until recently a point of contention, but was resolved though fate
mapping studies in mice that demonstrated conclusively that these cells in their entirety are descendants of
embryonic notochordal cells. During growth and aging, NP cells progressively lose their notochordal
characteristics to be replaced by smaller, chondrocyte-like “mature” NP cells. The disappearance of
notochordal cells has long been considered to contribute to progressive disc degeneration later in life, however
the underlying molecular mechanisms are not understood. With degeneration, the NP undergoes an
inflammation-mediated, fibrous transformation that compromises disc biomechanical function; however the
underlying cellular events that initiate and drive this process are poorly understood. Single cell RNA-Seq
(scRNA-Seq) is an emerging tool that permits high resolution transcriptome analysis of individual cells,
facilitating identification of rare subpopulations. In combination with cutting-edge computational tools, scRNA-
Seq can elucidate transitional states and relationships between cell subpopulations to predict cell
differentiation trajectories. The overall objective of this proposal is to use scRNA-Seq to investigate the
emergence of distinct NP cell subpopulations during intervertebral disc development and growth (Aim 1), and
establish the fate and function of these subpopulations during injury and degeneration (Aim 2). For both Aims,
using the top cluster-specific genes, the presence and localization of distinct NP cell subpopulations will be
confirmed using immunofluorescence and qPCR. The results of this study will have important implications for
the development of novel cell-based therapies for disc regeneration. For example, establishing NP progenitor-
specific markers through cluster-specific gene analysis may allow subsequent identification and enrichment of
therapeutic cell populations in human disc tissue, and defining differentiation trajectories may allow
reprogramming of such cells for therapeutic application.

## Key facts

- **NIH application ID:** 10401258
- **Project number:** 5R21AR077261-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Neil Malhotra
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $176,963
- **Award type:** 5
- **Project period:** 2021-05-05 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401258

## Citation

> US National Institutes of Health, RePORTER application 10401258, Dynamic heterogeneity of nucleus pulposus cells from development to degeneration (5R21AR077261-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401258. Licensed CC0.

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