The Potentials and Caveats of Mesenchymal Stromal Cell-Based Therapies in the Preterm Infant

Abstract

Preponderance of proinflammatory signals is a characteristic feature of all acute and resulting long-term morbidities of the preterm infant. The proinflammatory actions are best characterized for bronchopulmonary dysplasia (BPD) which is the chronic lung disease of the preterm infant with lifelong restrictions of pulmonary function and severe consequences for psychomotor development and quality of life. Besides BPD, the immature brain, eye, and gut are also exposed to inflammatory injuries provoked by infection, mechanical ventilation, and oxygen toxicity. Despite the tremendous progress in the understanding of disease pathologies, therapeutic interventions with proven efficiency remain restricted to a few drug therapies with restricted therapeutic benefit, partially considerable side effects, and missing option of applicability to the inflamed brain. The therapeutic potential of mesenchymal stromal cells (MSCs)—also known as mesenchymal stem cells—has attracted much attention during the recent years due to their anti-inflammatory activities and their secretion of growth and development-promoting factors. Based on a molecular understanding, this review summarizes the positive actions of exogenous umbilical cord-derived MSCs on the immature lung and brain and the therapeutic potential of reprogramming resident MSCs. The pathomechanistic understanding of MSC actions from the animal model is complemented by the promising results from the first phase I clinical trials testing allogenic MSC transplantation from umbilical cord blood. Despite all the enthusiasm towards this new therapeutic option, the caveats and outstanding issues have to be critically evaluated before a broad introduction of MSC-based therapies.

Bacterial Colonization within the First Six Weeks of Life and Pulmonary Outcome in Preterm Infants <1000 g

“…It is not surprising that clinical routine measures like the provision of breast milk and the reduction of antibiotic exposure are able to reduce the burden of BPD considering the impact on microbiota structures [ 21 , 22 , 24 , 25 , 56 ]. Tremendous hopes for substantial improvements to prevent BPD arise from innovative approaches like recombinant cytokine application and mesenchymal stem cell therapy [ 57 , 58 , 59 ]. Targeting the microbiota of the upper airway might also be efficacious.…”

The Microbiome and Preterm Birth: A Change in Paradigm with Profound Implications for Pathophysiologic Concepts and Novel Therapeutic Strategies

“…The reason for the so far unsuccessful establishment of effective therapeutic interventions is based on the complexity of the involved pathomechanisms. The complex interplay between different central pathways and persistent cell phenotype distortion after a one-time injury poses further obstacles that need to be bypassed to reach therapeutic efficiency [ 56 – 59 ]. The following sections are dedicated to the detailed description of some of the most important disease burdens provoked by microbial dysbiosis.…”

“…Bronchopulmonary dysplasia (BPD) is the chronic lung disease of the preterm infant leading to life-long limitations in lung function [ 59 ]. On a pathophysiologic level, BPD is characterized by distorted alveolar and vascular growth in the saccular stage of lung development.…”

Application of two different nasal CPAP levels for the treatment of respiratory distress syndrome in preterm infants—“The OPTTIMMAL-Trial”—Optimizing PEEP To The IMMAture Lungs: study protocol of a randomized controlled trial

“…To our surprise, no clinical trial since the introduction of nasal CPAP was conducted that assessed the efficacy of different PEEP levels during nasal CPAP treatment for RDS in the preterm population. Given the facts that the available strategies to avoid mechanical ventilation did not (yet) result in a reduction of BPD and are still associated with high treatment failure rates and that other promising strategies (i.e., cell based therapies) have to be critically evaluated before introduction into clinical practice, it seems conclusive to improve the effectiveness of the well-established CPAP therapy as the currently accepted gold standard of noninvasive respiratory support in VLBWI [28,29]. Our hypothesis is that the early application of a higher (6-8 cmH 2 O) versus a lower (3-5 cmH 2 O) PEEP range will more effectively recruit and maintain lung volumes in preterm infants with GA 26 + 0-29 + 6 weeks during the first 120 h of life and further reduce the need for mechanical ventilation and respiratory failure.…”