# Fibroblast lineage mechanisms of scarless skin healing

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $302,382

## Abstract

Project Summary
 As the U.S. and global populations continue to age, a concomitant increase disease is expected. The
increase will be in multiple diverse diseases, including post-surgical, post-traumatic, oncologic, and
degenerative diseases. Ultimately, the tissue response to disease and injury is fibrosis and scarring, which
degrades tissue function. The cost of this biomedical burden resulting from lost tissue function is enormous.
Alternative approaches for treatment of tissue scar and fibrosis must be developed, as no effective treatment
exists.
 The skin is an ideal system for understanding tissue regeneration as skin responds to injury with perfect
regeneration during fetal development. Understanding the mechanisms of skin regeneration in the fetus will
lead to development of regenerative treatment capabilities in the adult. Recent studies have focused on a
variety of wound healing mechanistic differences between scarless fetal wounds and scarring adult wounds.
These investigations range from growth factor expression, extracellular matrix deposition, and inflammation
differences. However the responsible mechanism(s) has not been identified. Our preliminary data has
identified a unique dermal fibroblast lineage that is the primary contributor to connective tissue secretion and
fibrotic scar formation during cutaneous wound repair. We believe that this lineage is responsible for skin scar
formation after injury.
 By determination of fibroblast lineages based on HOX gene expression during embryonic development, we
found that the Engrailed-1 (En1) lineage is the primary contributor to connective tissue secretion and
organization during embryonic development and cutaneous wound repair. Our central hypothesis is that
different lineages of dermal fibroblasts are responsible for scarless and scarring repair. In this proposal, we
will demonstrate that the En1 lineage of dermal fibroblast cells have a more fibrotic response during repair,
compared to non-lineage fibroblasts; and En1 lineage fibroblasts are responsible for the transition from
scarless healing to scarring repair in skin, due to a cell-intrinsic process. We will demonstrate that targeted
blocking of En1 lineage dermal fibroblast function during repair reduces scarring and induces regenerative
healing. We expect that therapeutic strategies will be developed to target these cells for specific tissue
regeneration after injury and disease rather than fibrotic tissue formation. We anticipate our findings to
significantly move the field of regenerative medicine forward. Furthermore, our findings will support the notion
that the term `fibroblast' represents a heterogeneous population of cells composed of multiple lineages, each
with distinct embryonic origins, migratory routes, and functional properties. These findings of fibroblast lineage
specificity will have a lasting and powerful impact as the mechanistic basis for investigation into fibroblast
lineage-specific response to injury is prov...

## Key facts

- **NIH application ID:** 9964833
- **Project number:** 5R01GM116892-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** MICHAEL T LONGAKER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $302,382
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964833

## Citation

> US National Institutes of Health, RePORTER application 9964833, Fibroblast lineage mechanisms of scarless skin healing (5R01GM116892-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9964833. Licensed CC0.

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