Pathophysiology of Perinatal Hypoxia-Ischemia and the Prospects for Repair from Endogenous and Exogenous Stem Cells

Learning Objectives

After completing this article, readers should be able to:

1. Compare the pathophysiology of hypoxia-ischemia (H/I) in preterm and term infants.

2. Delineate the differing effects of H/I on cells involved in development in the subventricular zone of the brain.

3. Describe the prospects for neural repair of neurons, oligodendrocytes, and projection neurons.

4. List the infants who are most likely to benefit from stem cell therapy to repair the brain.

Introduction

Perinatal hypoxia-ischemia (H/I) refers to exposure to low oxygen (hypoxia) and decreased blood flow (ischemia) prior to, during, or after birth and is regarded as a dominant cause of neurologic deficits in term and preterm infants. Numerous reviews have summarized the pathophysiology and histopathology of such insults and reviewed neuroprotective strategies. However, with accumulating evidence that many of these insults occur in utero, prevention may prove difficult, demanding that regenerative strategies be pursued to reduce the morbidity associated with the events. Therefore, in this review, we discuss the potential roles of endogenous and exogenous neural stem cells and progenitors in repairing the infant brain.

Incidence and Pathophysiology of Perinatal H/I

Perinatal H/I is an important clinical issue for both preterm and term infants. Approximately 55% of insults occur prior to or during birth as a result of underlying complications manifested prior to birth. (1) Despite major advances in obstetric care and management, the incidence of cerebral palsy, which has been associated with H/I, has remained at approximately 2 per 1,000 live births. (2)(3)(4) With advances in newborn intensive care, 80% of babies born extremely prematurely, during the second trimester, now survive, (5) but they often experience repeated hypoxic episodes. They have a 7% chance of developing cerebral palsy (5) and a 50% chance of developing motor, cognitive, and behavioral disorders. (6) A number of factors correlate highly with the occurrence of cerebral palsy, including proteinuria, …