Long-Lasting Paracrine Effects of Human Cord Blood Cells on Damaged Neocortex in an Animal Model of Cerebral Palsy

Abstract

Neonatal asphyxia is an important contributor to cerebral palsy (CP), for which there is no effective treatment to date. The administration of human cord blood cells (hUCBCs) is emerging as a therapeutic strategy for the treatment of neurological disorders. However, there are few studies on the application of hUCBCs to the treatment of neonatal ischemia as a model of CP. Experiments and behavioral tests (mainly motor tests) performed on neonatal hypoxia/ischemia have been limited to short-term effects of hUCBCs, but mechanisms of action have not been investigated. We performed a study on the use of hUCBCs in a rat model of neonatal hypoxia/ischemia and investigated the underlying mechanism for therapeutic benefits of hUCBC treatment. hUCBCs were intravenously transplanted into a rat model of neonatal hypoxia ischemia. hUCBCs increased microglia temporarily in the periventricular striatum in the early phase of disease, protected mature neurons in the neocortex from injury, paved the way for the near-normalization of brain damage in the subventricular zone (SVZ), and, in consequence, significantly improved performance in a battery of behavioral tests compared to the vehicle-treated group. Although the transplanted cells were rarely observed in the brain 3 weeks after transplantation, the effects of the improved behavioral functions persisted. Our preclinical findings suggest that the long-lasting positive influence of hUCBCs is derived from paracrine effects of hUCBCs that stimulate recovery in the injured brain and protect against further brain damage.

Evaluations of Intravenous Administration of CD34⁺ Human Umbilical Cord Blood Cells in a Mouse Model of Neonatal Hypoxic-Ischemic Encephalopathy

“…The large variation in infarct size makes the small morphological changes undetectable. Several studies on neonatal HIE have reported the beneficial effects of cell therapies in behavioral tests without any morphological improvement [11,36,37]. Such reports show that the lack of morphological improvement does not preclude an improvement in behavior.…”

Human allogeneic AB0/Rh-identical umbilical cord blood cells in the treatment of juvenile patients with cerebral palsy

“…Both UCB cells and cells derived as a result of their differentiation in vitro produce various neurotrophic factors, such as brain-derived neurotrophic factor, glialderived neurotrophic factor and neurotrophins 3 and 4-5 [9,10]. Additionally, UCB cells secrete an array of biologically active compounds (GRO-a, MIP-1a, MCP-1, MCP-3, RANTES, SDF-1, G-CSF, GM-CSF, interleukins [IL]-6 and -8) with neuroprotective, immunomodulating, anti-apoptotic and anti-inflammatory activities [11]. Presumably, paracrine regulation, including neuroprotection and stimulation of neurogenesis in the brain, is the major mechanism responsible for the therapeutic effect of systemic administration of UCB cells [12,42].…”

“…By producing neurotrophic factors, these cells may contribute to the regeneration of the central nervous system as regulators of neuronal and glial activity [11]. Both UCB cells and cells derived as a result of their differentiation in vitro produce various neurotrophic factors, such as brain-derived neurotrophic factor, glialderived neurotrophic factor and neurotrophins 3 and 4-5 [9,10].…”

Stem Cell Therapy for Neonatal Hypoxic–Ischemic Brain Injury

“…Inflammation would thereby be reduced in brain [33]. Bae et al [34] agreed that paracrine influences were the primary influence on intrinsic cell survival. Human umbilical cord blood cells reduced upregulation of CX43 and thereby brought about attenuation of reactive gliosis [35].…”