MSC Based Therapies to Prevent or Treat BPD-A Narrative Review on Advances and Ongoing Challenges.

Maurizio J Goetz,Cho-Ming Chao,Sarah Kremer,Harald Ehrhardt,Rory E Morty,Birte Staude,Judith Behnke,Lena Holzfurtner,Saverio Bellusci,Tayyab Shahzad

doi:10.3390/ijms22031138

Abstract

Bronchopulmonary dysplasia (BPD) remains one of the most devastating consequences of preterm birth resulting in life-long restrictions in lung function. Distorted lung development is caused by its inflammatory response which is mainly provoked by mechanical ventilation, oxygen toxicity and bacterial infections. Dysfunction of resident lung mesenchymal stem cells (MSC) represents one key hallmark that drives BPD pathology. Despite all progress in the understanding of pathomechanisms, therapeutics to prevent or treat BPD are to date restricted to a few drugs. The limited therapeutic efficacy of established drugs can be explained by the fact that they fail to concurrently tackle the broad spectrum of disease driving mechanisms and by the huge overlap between distorted signal pathways of lung development and inflammation. The great enthusiasm about MSC based therapies as novel therapeutic for BPD arises from the capacity to inhibit inflammation while simultaneously promoting lung development and repair. Preclinical studies, mainly performed in rodents, raise hopes that there will be finally a broadly acting, efficient therapy at hand to prevent or treat BPD. Our narrative review gives a comprehensive overview on preclinical achievements, results from first early phase clinical studies and challenges to a successful translation into the clinical setting.

Highlights

It has the potential to add a powerful strategy to the short list of available medications to prevent Bronchopulmonary dysplasia (BPD)
It is much too early to judge the ultimate efficacy in preterm infants, the congruent results obtained so far exclusively in rodent models are promising
Even a much lower efficacy in preterm infants can alleviate the tremendous disease burden of BPD where the best available medical approaches need a number of 10 treated infants to prevent one BPD case [12,20]

Summary

Introduction

Two subsequent pioneering studies published in 2010 paved the way towards the further evaluation of MSC to prevent or treat evolving BPD Both studies were performed in the hyperoxia exposure rodent model and provided convincing evidence that classical injury patterns of BPD provoked by the immature lung’s inflammatory response were reverted including lung alveolar and vascular structures, right ventricular hypertrophy, pulmonary function and hemodynamics [29,30]. Already at these early stages, it came clear that the beneficial effects of MSC were not mainly executed by cell transdifferentiation but by the MSC secretome when MSC cell culture supernatants were included into the series of experiments [30]. Attenuation of alveolar and vascular lung pathology reduction of formyl peptide receptor-1 expression and similar effects on apoptosis, VEGFA levels and influx of macrophages and neutrophils as in FPR-1 knockout mice [43]

Evaluation

Is MSC Application Safe?

Is the Secretome the Key to Practicality and Safety of MSC Application?

Is Cell Engineering the Ultimate Step to Therapy Success?

Concluding Remarks