Stem cell therapy to protect and repair the developing brain: a review of mechanisms of action of cord blood and amnion epithelial derived cells

Abstract

In the research, clinical, and wider community there is great interest in the use of stem cells to reduce the progression, or indeed repair brain injury. Perinatal brain injury may result from acute or chronic insults sustained during fetal development, during the process of birth, or in the newborn period. The most readily identifiable outcome of perinatal brain injury is cerebral palsy, however, this is just one consequence in a spectrum of mild to severe neurological deficits. As we review, there are now clinical trials taking place worldwide targeting cerebral palsy with stem cell therapies. It will likely be many years before strong evidence-based results emerge from these trials. With such trials underway, it is both appropriate and timely to address the physiological basis for the efficacy of stem-like cells in preventing damage to, or regenerating, the newborn brain. Appropriate experimental animal models are best placed to deliver this information. Cell availability, the potential for immunological rejection, ethical, and logistical considerations, together with the propensity for native cells to form teratomas, make it unlikely that embryonic or fetal stem cells will be practical. Fortunately, these issues do not pertain to the use of human amnion epithelial cells (hAECs), or umbilical cord blood (UCB) stem cells that are readily and economically obtained from the placenta and umbilical cord discarded at birth. These cells have the potential for transplantation to the newborn where brain injury is diagnosed or even suspected. We will explore the novel characteristics of hAECs and undifferentiated UCB cells, as well as UCB-derived endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs), and how immunomodulation and anti-inflammatory properties are principal mechanisms of action that are common to these cells, and which in turn may ameliorate the cerebral hypoxia and inflammation that are final pathways in the pathogenesis of perinatal brain injury.

Regenerative Potential of Intravenous Infusion with Mononuclear Cells in Cord Blood and G-CSF-Mobilized Peripheral Blood

“…In the neurologic field, many paracrine effects related to neurogenesis, myelination, angiogenesis, synaptogenesis, apoptosis, etc. have been demonstrated [5]. Although MSCs are generally isolated from BM or CB, these cells have also been reported to exist in PB.…”

Hypoxic-Ischaemic Encephalopathy and the Blood-Brain Barrier in Neonates

“…Their discovery led to the new concept of vasculogenesis [96] ; this is the development of new blood vessels by the recruitment and maturation of EPCs, in contrast to angiogenesis whereby new blood vessels are formed from proliferation of the pre-existing endothelium. Thus, it was hypothesized that harnessing the potential of EPCs in promoting neovascularization in the presence of ischaemic injury [97] would be valuable as a novel therapeutic intervention [98] . Indeed, several studies which have begun to assess the impact of the activation of EPCs in the presence of ischaemic injury have demonstrated that EPC treatment reduces infarct volume, improves deficits in cognitive learning and motor skills, and is associated with the recovery of regional cortical blood flow [99,100] .…”

Stem Cell Therapy in Pediatric Neurological Disabilities

“…Stem cells differentiate into neurons, oligodendrocytes and astrocytes which replace and repair the white matter injury in CP [17] (Figure 2). The growth factors secreted by these cells also help in remyelination, synaptogenesis, cytoprotection and angiogenesis which reverse the cellular injury in CP [18,19].…”