Exploring the Therapeutic Potential of Human Embryonic Stem Cells in Pediatric Neurotrauma

Funding Type: 
SEED Grant
Grant Number: 
RS1-00378
Investigator: 
ICOC Funds Committed: 
$0
oldStatus: 
Closed
Public Abstract: 
Traumatic brain injury (TBI) is a major cause of death (50,000/yr) and disability. The Centers for Disease Control and Prevention (CDC) has estimated that approximately 1.4-1.5 million Americans survive TBI annually. The economic burden of TBI in the United States has been estimated at approximately $56.3 billion in 1995. In children TBI has lifelong cognitive, physical, psychosocial/ behavioral/ emotional impairments since it interferes with the developing brain. In fact, in children deficits may not be fully revealed until later in life. TBI is among the most frequent pediatric neurological conditions (400,000 emergency department visits/yr; Langlois, 2001), occurring more frequently than cerebral palsy (10,000/yr), global developmental delay (80,000/yr) and epilepsy (30,000/yr). TBI continues to pose a serious health concern and adequate treatment for these injuries is seriously lacking. For example, the majority of TBI patients are discharged without subsequent health-care assistance. Among children aged 0-4 years 91% are unattended clinically post discharge (compare to 66% for all injuries). This is particularly discordant with data showing that at least 15% of TBI patients continue to experience negative consequences 1yr after injury (Guerrero et al, 2000). Optimistically, the neonatal brain may be more amenable than the adult brain to the therapeutic potential of stem cells. Transplantation studies using human embryonic stem cells and other stem cells have demonstrated their ability to facilitate functional recovery after brain and spinal cord injury. The proposed studies will determine the therapeutic capacity of neuron-enriched human embryonic stem cells (hESCs) to attenuate histological damage, normalize brain metabolite profiles, generate functional neural circuits and recover sensorimotor and memory functions following transplantation into postnatal rats subjected to lateral fluid percussion injury (FPI). The lateral FPI model most closely mimics postlesional events associated with TBI in humans (Dietrich et al, 1996). In Aim 1 we will evaluate whether hESCs (previously differentiated into neurons and labeled ferromagnetically) transplanted into the traumatically injured pediatric brain migrate to the site of injury and compensate for lesion area and brain metabolite changes using brain imaging methods. In Aim 2 accelerating rotarod and Morris water maze tests will be used to investigate whether grafted hESCs can ameliorate sensorimotor and cognitive deficits. In Aim 3 we will use immunohistochemical methods to label neural and glial phenotypes and synaptic contacts to determine if grafted hESCs form functional neuronal networks in injured brain. Our findings should eventually help promote the development of novel strategies to alleviate the effects of TBI. The proof of concept obtained in these studies will provide the necessary preliminary data and expertise necessary to be competitive for NIH funding.
Statement of Benefit to California: 
Traumatic brain injury (TBI) is a major cause of death (50,000/yr) and disability. The Centers for Disease Control and Prevention (CDC) has estimated that approximately 1.4-1.5 million Americans survive TBI annually. In contrast, the incidence of breast cancer and HIV/AIDS is 8 and 34 times lower (National Center for Injury Prevention and Control, CDC, http://www.cdc.gov/ncipc/factsheets/tbi.htm). The economic burden of TBI in the United States has been estimated at approximately $56.3 billion in 1995. In addition, TBI imposes enormous losses to individuals, their families, and society that cannot be completely enumerated. TBI is among the most frequent pediatric neurological conditions (400,000 emergency department visits; Langlois, 2001), occurring more frequently than cerebral palsy (10,000/year), global developmental delay (80,000/yr) and epilepsy (30,000/yr). TBI also accounts for significant neurological and neuropsychological morbidity in children. Data from 12 states, including California, indicate that the age-adjusted rate for TBI-related hospitalizations in 2002 was 79.0 per 100,000 population. While this estimate is ~20% lower than annual estimates for 1994-1995 from the National Hospital Discharge Survey (NHDS), TBI continues to leave an estimated 80,000-90,000 persons with long-term disability (Langlois et al, 2004). This apparent decline should be interpreted cautiously as estimates exclude non-residents and brain injuries not treated at hospitals. Most TBI cases are mild and deficits are subtle. In children deficits may not be fully revealed until later in life. TBI, which produces cognitive, physical and psychosocial/ behavioral/ emotional impairments, that often continue to develop for up to months and years after impact, continues to pose a serious health concern and adequate treatment for these injuries is seriously lacking. For example, the majority of TBI patients are discharged without subsequent health-care assistance. Among children aged 0-4 years 91% are unattended clinically post discharge (compare to 66% for all injuries). This is particularly discordant with data showing that at least 15% of TBI patients continue to experience negative consequences 1yr after injury (Guerrero et al, 2000). Optimistically, neonatal brain injury may be more amenable than the adult brain to the therapeutic potential of stem cells (Santner-Nanan et al, 2005). Transplantation studies using non-embryonic stem cells from human fetus, mouse embryonic stem cells have demonstrated their ability to facilitate functional recovery after brain and spinal cord injury. hESCs offer greater ability of pluropotency and can prevent any cross-species consequences. To date a very limited number of studies have explored the ability of hESCs to reverse or protect against detrimental and permanent effects of TBI, especially as measured noninvasively using brain imaging.

© 2013 California Institute for Regenerative Medicine