Neonatal-Perinatal medicine is one of the youngest subspecialties in medicine. The term Neonatology was coined in 1960 as more practitioners became interested in newborn care. The first sub-board examination in Neonatal-Perinatal medicine in the United States was conducted in 1975.1 Since then, the specialty's adoption of new treatment modalities has ebbed and flowed; with Neonatology being an early adopter of extra-corporeal life support, experiencing a rapid move from bench-to-patient. However, the patient population is quite unique, and while early outcomes from studied interventions maybe reassuring, some interventions had significant long-term complications; one such example has been the early and prolonged use of post-natal steroids to treat bronchopulmonary dysplasia (BPD). In the late 1980s and early 1990s early, prolonged, high-cumulative doses of Dexamethasone were used to facilitate weaning from respiratory support. This was heralded as a potential “cure” for BPD. It wasn't until at follow-up of survivors that a significant increase in neurodevelopmental impairment such as cerebral palsy (CP) was noted.2 Observations like these have proved that all interventions may have deleterious long-term effects in such a vulnerable population, and rigorous long-term safety profiles for therapies need to be established scientifically.

While the existence of stem cells (SC) was theorized prior to the establishment of cell theory,3,4 proper isolation of clonal cells was not achieved till 1963.5 The number of publications surrounding SC remained relatively low till the late 1990s after which interest in the field experienced near exponential growth, with more 38,000 published in 2021 as reported by PubMed (Fig. 1).

Like implementation of ECMO, steroid rescue therapies, inhaled nitric oxide, and many other interventions, Neonatology's initial interest in SC as therapeutic mediators is hard to pinpoint. The earliest references to SC in neonatal literature was initially surrounding their importance in developmental biology and embryology with emphasis on normal hematopoiesis and replenishment of the intestinal lining.6,7 Reports in the 1980s had suggested the utility of SC as therapeutic mediators in specific disease states. The interest in their ability to regenerate diseased neonatal lungs could be traced to a 2006 review paper by Van Haaften and Thebaud, with initial preclinical evidence for efficacy being provided in 2009.8,9

In this review, we will explore some of the preclinical and clinical evidence that exists for stem cell efficacy in neonatal diseases, and the barriers to translating this evidence into clinical trials and interventions (Fig. 2).