Treating Stress Urinary Incontinence with Human Embryonic Stem Cells

Funding Type: 
SEED Grant
Grant Number: 
RS1-00413
ICOC Funds Committed: 
$0
Disease Focus: 
Cancer
Neurological Disorders
Skeletal Muscle
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Urinary incontinence (UI) is a major health issue that affects more than 200 million people worldwide. Stress urinary incontinence (SUI), which accounts for half of all UI cases, is the involuntary loss of urine in the absence of a detrusor contraction. SUI occurs as a result of weakened muscles of the pelvic floor and urethra, producing urine loss whenever there is an increase of intra-abdominal pressure, such as coughing, sneezing, and laughing. Currently there is no effective treatment for SUI. Because weakened muscles and nerves in the urethra are the underlying cause of SUI, this proposed study seeks to correct such deficiencies by replenishing the affected urethra with human embryonic stem cells (hESC). Human ESC are capable of differentiating into various cell types including smooth muscle, striated muscle, and nerves. These cell types are also found in the urethra and are affected during the disease progression of SUI. In Specific Aim 1 of this proposed project we will investigate whether hESC can be induced to turn into cell types found in the healthy urethra. In Specific Aim 2 we will test the therapeutic efficacy of hESC. Because it is unethical to conduct this research in patients, we will employ a rat SUI model that was developed in our laboratory 11 years ago. We have shown in several publications that this SUI model closely mimics human SUI in both the disease progression and pathology. We are therefore confident that this rat model will allow us to assess the therapeutic effectiveness of hESC. This assessment will then help us to decide whether hESC is suitable for human therapy.
Statement of Benefit to California: 
Urinary incontinence (UI) is a major health problem worldwide; therefore, this proposed study will not just benefit California but the whole world. If there is anything specifically Californian, that would be the research team and the use of human embryonic stem cells (hESC) that are federally restricted. In other words, the research has the potential to strengthen California's leadership in both the UI and hESC research fields. In the long term this enhanced leadership may translate into economic gains for California such as investment in the biotech industry and health care system. If permitted by regulatory agencies at the federal and state levels, clinical trials for this stem cell therapy could perhaps be initiated in California and therefore benefit Californians firsthand.
Progress Report: 
  • We have undertaken an extensive series of studies to delineate the radiation response of human embryonic stem cells (hESCs) and human neural stem cells (hNSCs) both in vitro and in vivo. These studies are important because radiotherapy is a frontline treatment for primary and secondary (metastatic) brain tumors. While radiotherapy is quite beneficial, it is limited by the tolerance of normal tissue to radiation injury. At clinically relevant exposures, patients often develop variable degrees of cognitive dysfunction that manifest as impaired learning and memory, and that have pronounced adverse effects on quality of life. Thus, our studies have been designed to address this serious complication of cranial irradiation.
  • We have now found that transplanted human embryonic stem cells (hESCs) can rescue radiation-induced cognitive impairment in athymic rats, providing the first evidence that such cells can ameliorate radiation-induced normal-tissue damage in the brain. Four months following head-only irradiation and hESC transplantation, the stem cells were found to have migrated toward specific regions of the brain known to support the development of new brain cells throughout life. Cells migrating toward these specialized neural regions were also found to develop into new brain cells. Cognitive analyses of these animals revealed that the rats who had received stem cells performed better in a standard test of brain function which measures the rats’ reactions to novelty. The data suggests that transplanted hESCs can rescue radiation-induced deficits in learning and memory. Additional work is underway to determine whether the rats’ improved cognitive function was due to the functional integration of transplanted stem cells or whether these cells supported and helped repair the rats’ existing brain cells.
  • The application of stem cell therapies to reduce radiation-induced normal tissue damage is still in its infancy. Our finding that transplanted hESCs can rescue radiation-induced cognitive impairment is significant in this regard, and provides evidence that similar types of approaches hold promise for ameliorating normal-tissue damage throughout other target tissues after irradiation.
  • A comprehensive series of studies was undertaken to determine if/how stem cell transplantation could ameliorate the adverse effects of cranial irradiation, both at the cellular and cognitive levels. These studies are important since radiotherapy to the head remains the only tenable option for the control of primary and metastatic brain tumors. Unfortunately, a devastating side-effect of this treatment involves cognitive decline in ~50% of those patients surviving ≥ 18 months. Pediatric patients treated for brain tumors can lose up to 3 IQ points per year, making the use of irradiation particularly problematic for this patient class. Thus, the purpose of these studies was to determine whether cranial transplantation of stem cells could afford some relief from the cognitive declines typical in patients afflicted with brain tumors, and subjected to cranial radiotherapy. Human embryonic (hESCs) and neural (hNSCs) stem cells were implanted into the brain of rats following head only irradiation. At 1 and 4 months later, rats were tested for cognitive performance using a series of specialized tests designed to determine the extent of radiation injury and the extent that transplanted cells ameliorated any radiation-induced cognitive deficits. These cognitive tasks take advantage of the innate tendency of rats to explore novelty. Successful performance of this task has been shown to rely on intact spatial memory function, a brain function known to be adversely impacted by irradiation. Our data shows that irradiation elicits significant deficits in learning and spatial task recognition 1 and 4-months following irradiation. We have now demonstrated conclusively, and for the first time, that irradiated animals receiving targeted transplantation of hESCs or hNSCs 2-days after, show significant recovery of these radiation induced cognitive decrements. In sum, our data shows the capability of 2 stem cell types (hESC and hNSC) to improve radiation-induced cognitive dysfunction at 1 and 4 months post-grafting, and demonstrates that stem cell based therapies can be used to effectively to reduce a serious complication of cranial irradiation.

© 2013 California Institute for Regenerative Medicine