# Multiscale modeling of an inductive hair follicle microenvironment in engineered skin substitute

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2022 · $338,503

## Abstract

Engineered skin tissues must reproduce the biological and mechanical functions of their native counterparts if
they are to provide health benefits to society. However, engineered skin substitute (ESS) only fulfills basic skin
functions and fails to match the structural and biophysical characteristics of the human skin, such as missing
hair follicle and sweat gland, limiting its use in vivo. Their absences are due to a lack of functioning cell types
that instruct human keratinocytes in ESS to make a hair follicle and a lack of an in-depth understanding of
essential epithelial-mesenchymal interactions that drive hair follicle formation. In the case of hair follicle
engineering, the epithelial-mesenchymal interactions between keratinocytes and their immediate dermal
environment need to be precisely modulated to govern hair follicle lineage commitment. The major cell type that
constitutes a unique dermal “niche” is a specialized population of fibroblasts, which are located at the base of
the hair follicle, called the dermal papilla (DP), and are different from normal human dermal fibroblasts. However,
it is of great difficulty to isolate and expand human DP fibroblasts in vitro while maintaining their inductive capacity
for tissue engineering purposes. The long-term goal is to develop novel bioengineering approaches to produce
a fully functional human skin equivalent with normal microanatomy. The central hypothesis is that hair follicle
induction is an emergent property of skin constructs, which requires the interplay of multiple signals and cell
types in an inductive microenvironment. The objectives are to systemically explore how to create an inductive
microenvironment in ESS to induce hair follicle formation. To achieve this, we have devised a three-pronged
strategy addressing hair follicle bioengineering in ESS: 1) mimic the original niche by fabricating composite
keratinocyte-DP cell spheroids in micropatterned ESS; 2) enhance intercellular interactions by adding BMP6 and
3) drive the DP phenotype by re-activating master transcription factors. In the first aim, we will determine if multi-
cell type spheroids combined with premade hair canals can mimic a natural niche in ESS. We have developed
two 3D composite spheroid models and will determine whether they will allow DP fibroblasts to expand in vitro
while maintaining DP inductivity to induce hair follicles in a laser micropatterned skin substitute model. In the
second aim, we will determine the inductive functions of Bmp6 in stimulating hair follicle formation in ESS. We
will dissect the roles of Bmp6 in hair follicle formation and growth. In the third aim, we will determine whether
human DP fibroblasts can be reprogrammed to reestablish hair inductivity. We will assess whether in vitro genetic
reprogramming of human DP fibroblasts by CRISPRa-mediated expression of master transcription factors
promote the ability of composite keratinocyte-DP cell spheroids to induce hair follicles in ESS. This ...

## Key facts

- **NIH application ID:** 10341124
- **Project number:** 5R01AR077238-02
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Yuhang Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $338,503
- **Award type:** 5
- **Project period:** 2021-02-04 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10341124

## Citation

> US National Institutes of Health, RePORTER application 10341124, Multiscale modeling of an inductive hair follicle microenvironment in engineered skin substitute (5R01AR077238-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10341124. Licensed CC0.

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