Skin regeneration is accelerated by a lower dose of multipotent mesenchymal stromal/stem cells\u2014a paradigm change

Gertraud Eylert,Reinhard Dolp,Magdalena Holter,Lars-Peter Kamolz,Christopher Auger,Viola Reiner,Marc G Jeschke,Ingrid Lang-Olip,Alexandra Parousis,Richard Cheng

doi:10.1186/s13287-020-02131-6

Abstract

BackgroundMultipotent mesenchymal stromal/stem cell (MSC) therapy is under investigation in promising (pre-)clinical trials for wound healing, which is crucial for survival; however, the optimal cell dosage remains unknown. The aim was to investigate the efficacy of different low-to-high MSC dosages incorporated in a biodegradable collagen-based dermal regeneration template (DRT) Integra®.MethodsWe conducted a porcine study (N = 8 Yorkshire pigs) and seeded between 200 and 2,000,000 cells/cm2 of umbilical cord mesenchymal stromal/stem cells on the DRT and grafted it onto full-thickness burn excised wounds. On day 28, comparisons were made between the different low-to-high cell dose groups, the acellular control, a burn wound, and healthy skin.ResultWe found that the low dose range between 200 and 40,000 cells/cm2 regenerates the full-thickness burn excised wounds most efficaciously, followed by the middle dose range of 200,000–400,000 cells/cm2 and a high dose of 2,000,000 cells/cm2. The low dose of 40,000 cells/cm2 accelerated reepithelialization, reduced scarring, regenerated epidermal thickness superiorly, enhanced neovascularization, reduced fibrosis, and reduced type 1 and type 2 macrophages compared to other cell dosages and the acellular control.ConclusionThis regenerative cell therapy study using MSCs shows efficacy toward a low dose, which changes the paradigm that more cells lead to better wound healing outcome.

Highlights

After a skin injury, skin regeneration and wound healing of the epidermis and dermis are crucial to lowering the risk of infections associated with high mortality [1]
Clinical trials are being conducted to investigate wound healing using multipotent stromal cells as known as mesenchymal stem cells (MSCs) [1, 8] incorporated into Integra® (e.g., adipose, bone marrow, skinderived, umbilical cord)
Stem cell differentiation assays were performed to confirm the differentiation potential into the mesenchymal lineages [10], as recently described and shown using our published protocols in a parallel project using the same cells seeded on Integra® [10], both followed after confirming the paracrine in vitro effects of the extracted cells for wound healing in our lab as previously shown [29, 30]

Summary

Introduction

Skin regeneration and wound healing of the epidermis and dermis are crucial to lowering the risk of infections associated with high mortality [1]. Publications utilizing the DRT for wound healing include MSCs cell dosages that vary between 5000 and 2,000,000 cells/cm2 [9,10,11] and are tested on different models, such as rodents [11,12,13,14,15], pigs [9, 10, 16], and humans [17] These studies were either given cell dosages once [9, 10, 16, 18] or multiple times [11] on acute [9, 10, 16, 18] and chronic wounds [17] either on partial [18] or full-thickness [9, 10, 16] (burn) wounds, making comparisons even more difficult. The low dose of 40,000 cells/cm accelerated reepithelialization, reduced scarring, regenerated epidermal thickness superiorly, enhanced neovascularization, reduced fibrosis, and reduced type 1 and type 2 macrophages compared to other cell dosages and the acellular control

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