PhD student, Monash University
Looking at long term umbilical cord blood cell treatment for neonatal hypoxic ischemic brain injury
I am investigating the use of human umbilical cord blood as a treatment for hypoxic ischemic neonatal brain injury. This type of brain injury can arise following an adverse event in utero, during birth or after birth that restricts the amount of oxygen and blood supplying the brain. This event can lead to debilitating conditions, such as Cerebral Palsy, which is a permanent movement disorder which is quite often associated with impairment of motor skills, cognition and speech, among other things Umbilical cord blood is full of beneficial cells that could help reduce inflammation and repair vasculature in the brain following an adverse event at birth, such as a baby experiencing a lack of blood and oxygen due to compression of the umbilical cord. In my preclinical animal models of neonatal brain injury, I am delivering human umbilical cord blood and then assessing the behavioural and pathological outcomes of this treatment in the long term. Previous studies in this field have only looked at short term effects of this treatment, but my study is investigating the efficacy of umbilical cord blood treatment in the long term, which will allow us to see if the positive effect of these cells is maintained. Furthermore, I will also be investigating the long-term behavioural effects of this injury and cell treatment. This is crucial as motor and behavioural deficits that arise in children diagnosed with Cerebral Palsy generally present between the ages of 18-24 months, thus it is important to consider the long-term problems associated with this type of brain injury. My hope is that my proposed stem cell treatment will improve the behavioural and pathological outcomes of my preclinical model of neonatal brain injury. From this, I am hoping that we can move into clinical trials, and in the long run, use umbilical cord blood stem cells to treat babies with debilitating conditions such as cerebral palsy. In turn, this would improve the day to day life of these babies and children and help reduce the burden on the families and society.
Abstract: Perinatal hypoxic-ischemic brain injury and stroke in the developing brain remain important causes of chronic neurologic morbidity. Emerging data suggest that transplantation of umbilical cord blood-derived stem cells may have therapeutic potential for neuroregeneration and improved functional outcome. The pluripotent capacity of stem cells from the human umbilical cord blood provides simultaneous targeting of multiple neuropathologic events initiated by a hypoxic-ischemic insult. Their high regenerative potential and naïve immunologic phenotype makes them a preferable choice for transplantation. A multiplicity of transplantation protocols have been studied with a variety of brain injury models; however, only a few have been conducted on immature animals. Biological recipient characteristics, such as age and sex, appear to differentially modulate responses of the animals to the transplanted cord blood stem cells. Survival, migration, and function of the transplanted cells have also been studied and reveal insights into the mechanisms of cord blood stem cell effects. Data from preclinical studies have informed current clinical safety trials of human cord blood in neonates, and further work is needed to continue progress in this field.
Pub.: 16 Apr '13, Pinned: 08 Nov '17
Abstract: Cerebral palsy (CP) is the most frequent neurological disorder associated with perinatal injury of the developing brain. Major brain lesions associated with CP are white matter damage (WMD) in preterm infants and cortico-subcortical lesions in term newborns. Cell therapy is considered promising for the repair of brain damage. Human umbilical cord blood mononuclear cells (hUCB-MNCs) are a rich source of various stem cells that could be of interest in repairing perinatal brain damage. Our goal was to investigate the potential of hUCB-MNCs to prevent or repair brain lesions in an animal model of excitotoxic brain injury. We induced neonatal brain lesions using intracranial injections of ibotenate, a glutamate agonist, in 5-day-old rat pups. hUCB-MNCs were injected either intraperitoneally (i.p.) or intravenously (i.v.) soon or 24 h after ibotenate injection, and their neurological effects were assessed using histology and immunohistochemistry. hUCB-MNCs injected i.p. did not reach the systemic circulation but high amounts induced a significant systemic inflammatory response and increased the WMD induced by the excitotoxic insult. This effect was associated with a significant 40% increase in microglial activation around the white matter lesion. hUCB-MNCs injected i.v. soon or 24 h after the excitotoxic insult did not affect lesion size, microglial activation, astroglial cell density, or cell proliferation within the developing white matter or cortical plate at any concentration used. We demonstrated that hUCB-MNCs could not integrate into the developing brain or promote subsequent repair in most conditions tested. We found that the intraperitoneal injection of high amounts of hUCB-MNCs aggravated WMD and was associated with systemic inflammation.
Pub.: 25 May '12, Pinned: 08 Nov '17
Abstract: The young human brain is highly plastic and thus early brain lesions can lead to aberrant development of connectivity and mapping of functions. This is why initially in cerebral palsy only subtle changes in spontaneous movements are seen after the time of lesion, followed by a progressive evolution of a movement disorder over many months and years. Thus we propose that interventions to treat cerebral palsy should be initiated as soon as possible in order to restore the nervous system to the correct developmental trajectory. One such treatment might be autologous stem cell transplantation either intracerebrally or intravenously. All babies come with an accessible supply of stem cells, the umbilical cord, which can supply cells that could theoretically replace missing neural cell types, or act indirectly by supplying trophic support or modulating inflammatory responses to hypoxia/ischaemia. However, for such radical treatment to be proposed, it is necessary to be able to detect and accurately predict the outcomes of brain injury from a very early age. This article reviews our current understanding of perinatal injuries that lead to cerebral palsy, how well modern imaging might predict outcomes, what stem cells are yielded from umbilical cord blood and experimental models of brain repair using stem cells.
Pub.: 24 Sep '11, Pinned: 08 Nov '17
Abstract: Neonatal hypoxic-ischemic insults are a significant cause of pediatric encephalopathy, developmental delays, and spastic cerebral palsy. Although the developing brain's plasticity allows for remarkable self-repair, severe disruption of normal myelination and cortical development upon neonatal brain injury are likely to generate life-persisting sensory-motor and cognitive deficits in the growing child. Currently, no treatments are available that can address the long-term consequences. Thus, regenerative medicine appears as a promising avenue to help restore normal developmental processes in affected infants. Stem cell therapy has proven effective in promoting functional recovery in animal models of neonatal hypoxic-ischemic injury and therefore represents a hopeful therapy for this unmet medical condition. Neural stem cells derived from pluripotent stem cells or fetal tissues as well as umbilical cord blood and mesenchymal stem cells have all shown initial success in improving functional outcomes. However, much still remains to be understood about how those stem cells can safely be administered to infants and what their repair mechanisms in the brain are. In this review, we discuss updated research into pathophysiological mechanisms of neonatal brain injury, the types of stem cell therapies currently being tested in this context, and the potential mechanisms through which exogenous stem cells might interact with and influence the developing brain.
Pub.: 02 Nov '13, Pinned: 08 Nov '17