Stem cell-based therapies for the newborn lung and brain: Possibilities and challenges

Abstract

There have been substantial advances in neonatal medical care over the past 2 decades that have resulted in the increased survival of very low birth weight infants, survival that in some centers extends to 22 weeks gestational age. Despite these advances, there continues to be significant morbidity associated with extreme preterm birth that includes both short-term and long-term pulmonary and neurologic consequences. No single therapy has proven to be effective in preventing or treating either developmental lung and brain injuries in preterm infants or the hypoxic-ischemic injury that can be inflicted on the full-term brain as a result of in utero or perinatal complications. Stem cell-based therapies are emerging as a potential paradigm-shifting approach for such complex diseases with multifactorial etiologies, but a great deal of work is still required to understand the role of stem/progenitor cells in normal development and in the repair of injured tissue. This review will summarize the biology of the various stem/progenitor cells, their effects on tissue repair in experimental models of lung and brain injury, the recent advances in our understanding of their mechanism of action, and the challenges that remain to be addressed before their eventual application to clinical care.

Keywords: Bronchopulmonary dysplasia; Exosomes; Hypoxic-ischemic encephalopaty; Mesenchymal stem cells.

Figure. A schematic on the parallel actions of MSC treatment on injured lung or brain

Tissue injury precipitates an inflammatory response by activating microglia and lung macrophages to a pro-inflammatory state (red icons). MSC transplantation restores homeostasis mainly though paracrine actions. Among such actions are the repression or reversal of the pro-inflammatory state, resulting in a shift in the balance towards an anti-inflammatory state (green icons). In the anti-inflammatory state, endogenous resident stem cells can repair tissue more efficiently. A possible parallel mechanism, as preliminary reports suggest, could be that MSC factors act directly on endogenous stem cells, mobilizing them to proliferate and differentiate. The main functional vector in the MSC secretome are extracellular vesicles, including exosomes, and the therapeutic effects of MSC treatment can be efficiently recapitulated by cell-free, exosomes-based treatment. (A): Biogenesis of exosomes in MSC multivesicular bodies (MVB) and release upon fusion of the MVB with the plasma membrane. (B): Uptake of MSC exosomes by a lung macrophage, and release of the exosomal cargo (X) into the recipient cell. N: nucleus.