The Potential of Stem Cell Therapy to Repair White Matter Injury in Preterm Infants: Lessons Learned From Experimental Models

Abstract

Diffuse white matter injury (dWMI) is a major cause of morbidity in the extremely preterm born infant leading to life-long neurological impairments, including deficits in cognitive, motor, sensory, psychological, and behavioral functioning. At present, no treatment options are clinically available to combat dWMI and therefore exploration of novel strategies is urgently needed. In recent years, the pathophysiology underlying dWMI has slowly started to be unraveled, pointing towards the disturbed maturation of oligodendrocytes (OLs) as a key mechanism. Immature OL precursor cells in the developing brain are believed to be highly sensitive to perinatal inflammation and cerebral oxygen fluctuations, leading to impaired OL differentiation and eventually myelination failure. OL lineage development under normal and pathological circumstances and the process of (re)myelination have been studied extensively over the years, often in the context of other adult and pediatric white matter pathologies such as stroke and multiple sclerosis (MS). Various studies have proposed stem cell-based therapeutic strategies to boost white matter regeneration as a potential strategy against a wide range of neurological diseases. In this review we will discuss experimental studies focusing on mesenchymal stem cell (MSC) therapy to reduce white matter injury (WMI) in multiple adult and neonatal neurological diseases. What lessons have been learned from these previous studies and how can we translate this knowledge to application of MSCs for the injured white matter in the preterm infant? A perspective on the current state of stem cell therapy will be given and we will discuss different important considerations of MSCs including cellular sources, timing of treatment and administration routes. Furthermore, we reflect on optimization strategies that could potentially reinforce stem cell therapy, including preconditioning and genetic engineering of stem cells or using cell-free stem cell products, to optimize cell-based strategy for vulnerable preterm infants in the near future.

Keywords: brain development; cell therapies; mesenchymal stem cells; myelin loss; preterm birth; regeneration; white matter injury; white matter pathology.

FIGURE 1

Developmental timeline comparing oligodendrocyte (OL) stage-specific development in different species. Blue bars depict late OL precursor cells (OPC), green bars depict pre-myelinating precursors (pre-OLs), and red bars depict mature OLs. From left to right: rodent, sheep, and human. The postnatal window in rodent OL development between postnatal day (P1–P14) corresponds to the latter half of human gestation [data are based on (Craig et al., 2003) and (Salmaso et al., 2014)]. Fetal sheep OL development between 70 and 145 gestational days (GD) approximately corresponds with late second and third human trimester [data based on (Back et al., 2012)]. Human OL development is based on data from Back et al. (2001). The intensity of the bar indicates the peak of OL development. Note that OL development of human extreme preterms (24–28 weeks of gestation) roughly corresponds to rodent P2 to P5 and ovine 90–95 GD. Also note that sheep and human OL development are roughly comparable, whereas rodent OL development is slightly different regarding time-window of OL development and composition of OL subtypes per postnatal/gestational age (Craig et al., 2003).

FIGURE 2

Illustration summarizing the possible working mechanisms of mesenchymal stem cells (MSCs). This illustration is based on the literature discussed in this review. MSCs are believed to exert their regenerative potential through reciprocal transport via gap junctions (blue), production of extracellular matrix proteins (pink), such as laminin, and transport via nanotubes (green). In addition, MSCs are able to release microvesicles (top, small vesicles) and exosomes (bottom, larger vesicles). These vesicles contain a mix of miRNA, cytokines and trophic factors, and mitochondria. MSCs can also directly have paracrine effects on neighboring cells by release of trophic factors and cytokines. Direct cell contact and the MSCs’ secretome can (1) dampen (red inhibitory arrow) the immune response in the periphery and central nervous system (CNS) (astrocyte in green; microglia in orange; neutrophil left top; and macrophage right bottom). The MSCs’ secretome can also (2) directly inhibit apoptosis of pre-myelinating OL (pre-OL; irregular shaped purple cell), whereas it can also (3) directly stimulate (green stimulatory arrow) pre-OL differentiation toward myelinating mature OLs (middle and right purple cells). As neuroinflammation will (4) increase pre-OL apoptosis, and (5) inhibit pre-OL maturation [lower stimulatory arrow (green) and lower inhibitory arrow (red), respectively], MSCs can also indirectly reduce pre-OL apoptosis and stimulate pre-OL maturation by dampening neuroinflammation.