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Therapeutic reversal of radiotherapy injury to pro-fibrotic dysfunctional fibroblasts in vitro using adipose-derived stem cells
Shukla, Lipi Luwor, Rodney B. Ritchie, Matthew E Akbarzadeh, Shiva Zhu, Hong-Jian Morrison, Wayne Karnezis, Tara Shayan, Ramin
Shukla, Lipi
Luwor, Rodney B.
Ritchie, Matthew E
Akbarzadeh, Shiva
Zhu, Hong-Jian
Morrison, Wayne
Karnezis, Tara
Shayan, Ramin
Abstract
Background:
Cancer patients often require radiotherapy (RTx) to enhance their survival. Unfortunately, RTx also damages nearby healthy non-cancer tissues, leading to progressive fibrotic soft-tissue injury, consisting of pain, contracture, tissue-breakdown, infection, and lymphoedema. Mechanisms underlying the clinically observed ability of fat grafting to ameliorate some of these effects, however, are poorly understood. It was hypothesized that RTx significantly alters fibroblast cell function and the paracrine secretome of adipose-derived stem cells (ADSC) may mitigate these changes.
Methods:
To investigate cellular changes resulting in the fibrotic side-effects of RTx, cultured normal human dermal fibroblasts (NHDF) were irradiated (10Gy), then studied using functional assays that reflect key fibroblast functions, and compared with unirradiated controls. RNA-Seq and targeted microarrays (with specific examination of TGFβ) were performed to elucidate altered gene pathways. Finally, conditioned-media from ADSC was used to treat irradiated fibroblasts and model fat graft surgery.
Results:
RTx altered NHDF morphology, with cellular functional changes reflecting transition into a more invasive phenotype: increased migration, adhesion, contractility, and disordered invasion. Changes in genes regulating collagen and MMP homeostasis and cell-cycle progression were also detected. However, TGFβ was not identified as a key intracellular regulator of the fibroblast response. Finally, treatment with ADSC-conditioned media reversed the RTx-induced hypermigratory state of NHDF.
Conclusions:
Our findings regarding cellular and molecular changes in irradiated fibroblasts help explain clinical manifestations of debilitating RTx-induced fibrosis. ADSC-secretome-mediated reversal indicated that these constituents may be used to combat the devastating side-effects of excessive unwanted fibrosis in RTx and other human fibrotic diseases.
Keywords
Date
2020
Type
Journal article
Journal
Plastic and Reconstructive Surgery - Global Open
Book
Volume
8
Issue
3
Page Range
1-9
Article Number
Article e2706
ACU Department
School of Behavioural and Health Sciences
Faculty of Health Sciences
Faculty of Health Sciences
Relation URI
Source URL
Event URL
Open Access Status
Published as ‘gold’ (paid) open access
License
CC BY-NC-ND 4.0
File Access
Open