Stem cell therapy for neonatal hypoxic-ischemic encephalopathy

Abstract

Treatments for neonatal hypoxic-ischemic encephalopathy (HIE) have been limited. The aim of this paper is to offer translational research guidance on stem cell therapy for neonatal HIE by examining clinically relevant animal models, practical stem cell sources, safety and efficacy of endpoint assays, as well as a general understanding of modes of action of this cellular therapy. In order to do so, we discuss the clinical manifestations of HIE, highlighting its overlapping pathologies with stroke and providing insights on the potential of cell therapy currently investigated in stroke, for HIE. To this end, we draw guidance from recommendations outlined in stem cell therapeutics as an emerging paradigm for stroke or STEPS, which have been recently modified to Baby STEPS to cater for the "neonatal" symptoms of HIE. These guidelines recognized that neonatal HIE exhibit distinct disease symptoms from adult stroke in need of an innovative translational approach that facilitates the entry of cell therapy in the clinic. Finally, new information about recent clinical trials and insights into combination therapy are provided with the vision that stem cell therapy may benefit from available treatments, such as hypothermia, already being tested in children diagnosed with HIE.

Keywords: cerebral palsy; combination therapy; hypothermia; stem cells; translational research.

Figure 1

Multiple intended combination therapies are shown for three different groups: acute (0–48 h after birth), subacute (6–72 h after birth), or chronic (>72 h after birth). The joint effort of both cell transplantation therapy and neuroprotective therapies, such as hypothermia, erythropoietin (EPO), and helium are used for treating neonates with HIE. When treating the neonate in the acute or subacute phase, the treatment is referred to as neuroprotection. On the other hand, treatments aimed at the chronic stage are referred to as neurorestoration. EPO or helium is used to treat the subject during the acute phase, while hypothermia and stem cell therapy is used to treat the subacute stage via intravascular routes. When treating the chronic stage, stem cell therapy is used via intracerebral route, which stimulates the neurorestorative mechanisms. The combination of these therapies may prove to be effective in neonates suffering from HIE.