Thursday, March 31, 2016

Stem CellsThroughout the globe, the number of elderly individuals continues to increase, with a concomitant rise in life span.

In large developing nations, such as China and India, the number of elderly individuals over the age of 65 will increase from current levels of approximately 5% to almost 10% of the population over the next several years. In developed nations, the number of individuals over the age of 65 has doubled during the prior 50 years (1). Life expectancy is increasing in countries such as the United States and is accompanied by a 1% decrease in the age-adjusted death rate from the years 2000 through 2011 (2). Improvements in health care and stable nutritional environments are important factors for the increased longevity of the global population.

Despite advances in medical care, multiple disorders continue to affect the global population with increased morbidity and mortality.

With regard to noncommunicable diseases, the five leading causes of death are cardiac disease, cancer, chronic lower respiratory disease, stroke, and traumatic accidents. The World Health Organization reports that nearly 80% of these noncommunicable diseases occur in low- and middle-income countries (3). Noncommunicable diseases affect almost 30% of the population under the age of 60 in low- and middle-income countries. Such data provide a clear contrast with high-income countries, where noncommunicable diseases significantly affect approximately 10% of the population under the age of 60. Yet metabolic disorders affect large portions of the populations in both low- and high-income countries. For example, approximately 350 million individuals worldwide currently have diabetes mellitus.

It is also interesting to note that there exists a rise in the incidence of neurodegenerative disorders throughout the globe. Acute and chronic neurodegenerative disorders are believed to result in disability and death in more than 30 million individuals worldwide. Chronic neurodegenerative disorders such as the sporadic form of Alzheimer’s disease can certainly affect a large proportion of the global population. Acute neurodegenerative disorders also place a severe burden on the world’s population. Stroke leads to multiple complications that affect both the livelihood and minimal daily function of an individual. In addition, noncommunicable diseases such as cardiovascular disease and diabetes mellitus affect multiple systems of the body and can contribute to the onset of acute neurodegenerative disease that include stroke. Traumatic brain injury also leads to neurological disability and death throughout the world and can have a twofold effect to result in acute injury to the nervous system as well as subsequent chronic neurodegenerative impairment that may lead to death.

Given the severity of the disorders that affect the world’s population and the degree to which these disorders are rising in incidence with the increased life span of the global population, what potential targets should be considered to develop effective strategies against a complex set of clinical disorders?

At present, numerous therapeutic strategies are under development for multiple clinical entities. However, some of the most novel and most exciting considerations to date involve the application of stem cells for new clinical treatments for patients. Targeting stem cell proliferation is being considered for multiple disorders that involve the nervous system, visual pathways, the cardiovascular system, the immune system, metabolism, and cancer. Just recently, new work has defined a role for lens epithelial stem/progenitor cells in the body to lead to functional eye lens regeneration in human infants for the treatment of cataracts (4). One of the most vexing problems for treatments that rely on stem cells is the ability to control the proliferation of stem cells and maintain viable stem cell populations in the body. New avenues of research are focusing on vital cellular pathways throughout the body to oversee stem cell proliferation that employ specific proteins, such as the mechanistic target of rapamycin (mTOR) and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1).

These proteins and the genes that direct their production are critical to multiple systems throughout the body and therefore can significantly affect multiple disease entities. In particular, mTOR has been found necessary in neural stem cells to promote lineage expansion and neuronal cell production in the brain. During aging, it has been observed that activity of mTOR may be reduced and that this loss in mTOR activity leads to reduced neurogenesis and a reduction in the proliferation of active neural stem cells in the brain. This loss of mTOR activity may result in dementia and Alzheimer’s disease and lead to permanent disability during acute injury with stroke or trauma. Equally important is the role of SIRT1 for stem cells. SIRT1 also promotes neuronal growth in the brain, fosters endothelial progenitor cell survival for blood vessel repair throughout the body, and can improve cardiomyoblast survival in the heart that may repair injury during myocardial infarction.

How do we “translate” knowledge of critical cellular pathways such as mTOR and SIRT1 into effective stem cell treatments for patients?

When considering the modulation of stem cell growth, it is important to recognize that a fine biological control must be in place to oversee pathways such as mTOR and SIRT1. This is somewhat similar to confirming that patients receive proper dosing of a particular medication to ensure that treatments are effective and that potential toxic side effects are reduced or eliminated. For example, as a growth agent, significantly increased activity of SIRT1 under some circumstances can lead to the expansion of cancer stem cells and result in unwanted tumor cell growth in the body. Recently, new work is focusing on pathways to precisely regulate SIRT1 activity and stem cell proliferation for effective translation into clinical treatment programs for patients. These strategies directly control ribonucleic acids (RNAs) in the body and involve the modulation of microRNAs (miRNAs). MiRNAs are small, noncoding RNAs that are ubiquitous in the body and consist of 19–25 nucleotides.

MiRNAs form complementary base-pairing sequences with other messenger RNAs (mRNAs) in the body that effectively silence and block these mRNAs from producing proteins. As a result, miRNAs can act as agents to control the activity of specific proteins such as SIRT1 and offer important insights to potentially modulate proliferative pathways that involve stem cell proliferation and disease resolution. Increased activity and expression of distinct miRNAs can be beneficial for stem cell growth for neurons in the brain and, at the same time, limit the growth of non-neuronal cells that may lead to fibrotic tissue and the eventual loss of functional nerve networks after injury. Furthermore, limited activity of mTOR or SIRT1 through the targeting of miRNAs may be required to promote the development of stem cells into brain cells, a process predicted to be necessary for memory enhancement and return of previously lost cognitive function.

Overall, targeting miRNAs provides an intriguing format for the control of vital cellular pathways that can affect stem cell treatments in the body.

Stem cells, miRNAs, mTOR, and SIRT1 hold great promise for the future to address multiple disorders for the global population. However, to effectively translate our knowledge of these pathways into new drug discoveries, further work is required at this time. For instance, mTOR and SIRT1 do not equally affect all cell types throughout the body, indicating that these pathways may not always be beneficial in all cell types. As an example, depending upon the cell type, SIRT1 has the capability to either promote or retard stem cell growth that may lead to unwanted side effects. In particular, SIRT1 can promote the growth of acute myeloid leukemia stem cells, result in resistance against chemotherapy during cancer treatments, and foster oncogenic transformation and cancer growth of neural stem cells in the brain.

On the flip side, insufficient SIRT1 activity may not provide effective protection to the cardiovascular system during myocardial infarction in patients. Therefore, additional insight, time, and effort are necessary to bring this cutting-edge knowledge forward into the clinic that employ carefully designed clinical trials that are targeted to appropriate disorders and patients. Future work that can precisely navigate stem cell proliferation can open new avenues for the treatment of hosts of a growing number of noncommunicable diseases that currently affect the world’s population.

References

1.         Hayutin A. Global demographic shifts create challenges and opportunities. Pension Real Estate Association Quarterly. 2007;Fall:46–53.

2.         Miniño AM. Death in the United States, 2011. National Center for Health Statistics data brief. March 2013;115:1–8. PMID: 23742756. Epub June 8, 2013.

3.         World Health Organization. Description of the global burden of NCDs, their risk factors, and determinants. Global Status Report on Noncommunicable Diseases 2010. Geneva, Switzerland: World Health Organization; April 2011:1–176.

4.         Lin H, Ouyang H, Zhu J, Huang S, Liu Z, Chen S, et al. Lens regeneration using endogenous stem cells with gain of visual function. Nature. March 9, 2016. PMID: 26958831. doi:10.1038/nature17181. Epub March 10, 2016.


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