Author ORCID Identifier

orcid.org/0000-0001-5851-255X

Date of Graduation

5-2018

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Raghu Kalluri

Committee Member

Menashe Bar-Eli

Committee Member

Valerie LeBleu

Committee Member

Mikhail Kolonin

Committee Member

Samuel Mok

Abstract

Impaired wound healing can lead to excessive scarring, dehiscence, chronic ulcers, and infection, which have adverse impact on the quality of life and pose a significant economic burden on the health care system. Thus, new therapeutic approaches are critically important. Dermal fibroblasts are critical players in cutaneous wound healing, possibly lending their contractile properties and extracellular matrix (ECM) remodeling functions to promote effective tissue repair. Dermal fibroblasts are also postulated to orchestrate tissue repair by interacting with and controlling other cell types in the wound microenvironment. It has become increasingly clear that the generic term “fibroblast” encompasses a diverse cell population with distinct origins and heterogeneous functions. Fibroblast heterogeneity is in part exemplified by the numerous expression markers used to distinguish them. The overarching goal of this study is to precisely define the heterogeneity of dermal fibroblasts and unravel their functional roles during cutaneous wound healing process.

In order to decipher the dynamics of fibroblast marker composition during the wound repair process we utilized multiplexed immunolabeling platforms in order to quantify the expression of multiple fibroblast markers within a single tissue. Using this approach, along with lineage tracing studies, we observed that a population of resident dermal fibroblasts in normal skin, labeled with FSP1/S100A4, acquire the myofibroblast phenotype associated with acquisition of ⍺SMA expression. Importantly, not all ⍺SMA+ cells arose from FSP1/S100A4+ progenitors, indicating that there exist at least two populations of fibroblasts which contribute to the pool of activated myofibroblasts during tissue repair.

Further experimentation was carried using transgenic mouse models which allow selective depletion based on expression of fibroblast markers such as ⍺SMA, FSP1/S100A4, FAP, and Collagen1⍺1. Using these models, we were able to identify unique phenotypes associated with depletion of these populations in the context of wound repair. While depletion of ⍺SMA+ cells resulted in a complete inability to re-epithelialize, results from other depletion models were more nuanced, affecting collagen deposition, revascularization, and dermal thickness.

The work presented here offers novel insights on the dynamic nature of wound healing fibroblasts and proposes new avenues for the treatment of chronic wounds.

Keywords

wound healing, fibroblast, heterogeneity, repair

Available for download on Saturday, May 04, 2019

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