Interaction between transplanted human embryonic stem cell-derived neuronal precursors and endogenous neurogenesis in ischemic brain
Acute and chronic neurodegenerative diseases are common, disabling, and poorly responsive to current treatment. Stroke, the most frequent cause of acute neurodegeneration, has a prevalence of about 5 million and an incidence of approximately 700,000 individuals per year in the United States, where it is the third leading cause of death. Even among those who survive stroke, disability due to limb weakness, gait disorders, language impairment and other deficits is common, and roughly 20% of patients require institutional care at 6 months post-stroke. This long-term disability contributes to the average lifetime cost for stroke care of nearly $150,000 and an annual national cost of over $50 billion. The most recent major advance in treatment, the use of thrombolytic agents to dissolve clots in the acute aftermath of stroke, is limited in impact because it appears to be effective only within about the first 3 hours after onset of symptoms.
Clinical manifestations of acute and chronic neurodegenerative diseases, including stroke, result primarily from irreversible cellular (especially neuronal) dysfunction and, eventually, cell death. Based on this experience, it is reasonable to conclude that cell-replacement therapy, technically challenging though it may be, is worth pursuing. In addition to the prospect of more completely restoring brain function, cell-replacement therapy has the further advantage that it might be effective at later stages of a disease. This is an important consideration not only in disorders like stroke, which often evolve too quickly for acute treatment to be instituted, but also in chronic neurodegenerations, where cell loss may already be extensive before the onset of symptoms.
At least two approaches to nerve cell replacement are possible. First, the brain itself generates new nerve cells throughout life. Their production is increased following stroke and is associated with migration of these new cells to affected brain regions. Moreover, blocking this process impairs recovery, suggesting that it is important for brain repair. A second approach involves cell transplantation from external sources, including human embryonic stem cells. Advantages of this strategy include the ability to expand and mature cells in vitro, engineer cells, and deliver cells directly to sites of injury. A critical step in assessing the feasibility of this approach in stroke is to understand the interaction between transplanted human embryonic stem cells and the stroke brain. We propose to investigate this interaction, and hypothesize that it may help determine the success of cell replacement in the brain following stroke, and that its modification may help optimize the neurotransplantation therapy.
In November 2002, the California Department of Health Services published a report titled, “Heart Disease and Stroke in California: Surveillance and Prevention”. The report showed that in 1999, 96,208 Californians had been hospitalized for stroke. The majority (54%) were women and almost 25% were under age 65. The average length of stay was 8 days, and the cost averaged $2,555 per day, accounting for total hospital charges of $2.1 billion.
Although the age-adjusted rate for death from stroke in California had decreased in the two decades leading up to 1999, stroke still accounted for 18,079 deaths, or 8% of all deaths in the state. Stroke death rates were higher in African-Americans than in other ethnic groups. And while the prevalence of certain stroke risk factors, like hypertension, had declined, others, including diabetes and hypercholesterolemia, were increasing.
Californians, like others, have very limited treatment options once stroke occurs. If they are lucky enough to arrive within about three hours post-stroke at one of eighteen primary stroke centers in the state accredited by the Joint Commission on Accreditation of Healthcare Organizations, they may be candidates for thrombolytic therapy, which can dissolve the clot responsible for their symptoms. However, many patients do not arrive at the hospital quickly enough to benefit from this form of therapy, and some of those who do suffer bleeding complications.
The fact that patients with stroke usually improve spontaneously for up to about three months after the event suggests that the brain is conducive to at least some degree of repair. If spontaneous improvement is incomplete, it might be possible to intervene to enhance recovery. Although many such interventions may be possible, the fact that cell loss is such a prominent feature of stroke implies that cell replacement therapy could be a useful approach. This proposal explores that possibility, by investigating the interaction between the brain’s own cell-replacement mechanism and the transplantation of new nerve cells derived from human embryonic stem cells.