Explaining Stem Cells and Endothelial Progenitor Cells (EPC)
1. What is endothelium?
Endothelium is the inner lining of the blood vessels
2. What is the role of the endothelium as it relates to the vital processes important to maintaining vascular health?
· Controls blood pressure and clotting mechanisms
· Acts as a selective barrier between the blood stream and the interior of the blood vessels, thus playing a role in the body’s immune function and inflammatory process
· Aids in tissue remodeling and the formation of new blood vessels
3. What is endothelial dysfunction?
A compromise in the normal function of the endothelium resulting in:
· A decrease in vasodilation of the endothelium
· Risk for inflammation and clotting are increased
· A higher risk of major life threatening diseases such cardiovascular disease, namely atherosclerosis: a buildup of a waxy plaque on the inside of blood vessels
· Loss in mental, sexual, visual, cardiovascular and respiratory function as seen in age associated deterioration
4. What causes the endothelial dysfunction?
Factors ranging from disease processes such as septic shock, high blood pressure, high cholesterol levels, diabetes, obesity to environmental factors such as smoking and exposure to air pollution.
5. What tests can measure a decrease in endothelial function?
Certain tests such as the Flow Mediated Dilation (FMD) assay can determine the condition of the endothelium. This test measures the characteristics of the blood vessel wall and explores endothelial function.
6. What is the significance of the results based from the FMD assay?
Studies done to determine endothelial health can show if there is a dysfunction in conditions such as healthy aging, as well as various inflammatory states including kidney failure, rheumatoid arthritis, Crohn’s disease, diabetes, heart failure and Alzheimers. Although still under investigation, low FMD scores have been associated with clots, atherosclerosis and inflammation. These problems can increase the chance of potentially harmful or life threatening conditions. Also, as a result of the aging process, new blood vessel growth is slowed. However, research suggests that endothelial damage can be repaired with the help of endothelial progenitor cells (EPC).
7. What is an Endothelial progenitor Cell?
An endothelial progenitor cell (EPC) is a cell that is able to mature into a new healthy endothelial.
8. What is the significance of a EPC as seen in mice studies?
As part of initial investigations, EPCs have been shown to reverse endothelial deterioration
· Studies using mice with a genetic predisposition to developing atherosclerosis were introduced to labeled bone marrow stem cells; resulting in new endothelial cells.
· In another experiment, 3 month old identical cardiac grafts were implanted into 18 month old mice. One received 18 month old bone marrow mononuclear cells while the other received 3 month old cells. Successful implantation and survival was seen in the graft receiving younger bone marrow mononuclear cells, suggesting that younger cells are better than older cells.
Because defined markers of human EPC exist, scientists are leaning towards the idea of EPC centered therapies based from results conducted using animal studies that showed improvement in vascular function.
9. How does EPC work in acute injuries?
Certain chemicals released during tissue injury and low oxygen levels such as stroke, heart damage or contusion, are said to release EPC to the involved areas.
· In heart attack cases, EPC mobilization is stimulated as a response to injury through the release of certain cells called CD34, which resemble endothelium and express its’ markers. The blood drawn from patients who experienced a recent heart injury (<12 hours) was shown to have elevations of these cells when compared to other populations.
· Research involving stroke has shown that EPC are released in response to injury and aids in recovery. Comparison studies between patients with acute stroke and healthy volunteers suggest that lowered levels of EPC can predict the extent of neurologic damage. However, these studies have yet to prove the therapeutic effect of mobilized EPC, though animal studies have shown a desired outcome with respect to the administration of EPC.
· In the case of ARDs, circulating EPC has been shown to restore injured lung tissue. Many correlations between injury and infection versus an increase in circulatory EPCs have been made such as seen in pneumonia, fibrosis and lung damage.
· A study involving septic patients showed that survival was increased with elevated EPCs. Activated Protein C, the only effective drug against sepsis, works alongside with endothelial protection, illustrating that low EPC levels are associated with a higher chance for death.
10. How does chronic inflammation affect circulating EPC?
Inflammation lowers the amount of EPC due to stress of injury, concluding that administration of EPC progenitors in inflammatory conditions may have therapeutic effects.
During inflammation the regeneration of tissue and blood vessels occur. Consequently, this process may cause inflammation to worsen in an attempt to reverse the original damage. Examples of this occurrence include: plaque formation from tissue overgrowth, responding to injury in the heart’s blood vessel walls; excess development of scar tissue in the liver rather than normal renewal; and the remodeling of the heart muscle after a sustained heart attack leading to heart failure.
In these situations there is a lack of EPC and regenerative cells, signifying that the overwhelming demands of the body to heal itself may lead to a decrease in EPC. This exhaustion, as a result, decreases the amount of EPC numbers and slows the healing process.
11. What are the beneficial effects of EPC as seen in inflammatory conditions?
The administration of EPC in several experiments has been shown to have a therapeutic effect on disease progression. For example, its’ administration has been shown to: decrease balloon injury of the heart, suppress the liver from scarring and prevent the heart from remodeling itself after a heart attack. Although there is no defining evidence that EPC is in the fact the variable for regeneration, evidence supports that EPC appears to play a role in the healthy regeneration of injured or damaged tissue.
12. What is the reason for inflammation in various conditions?
The inflammation seen in organ degenerative conditions such as heart, kidney, liver failure to autoimmune conditions such as rheumatoid arthritis and Crohn’s Disease to healthy aging all appear to share increases in certain inflammatory markers, which directly suppress EPC production or activity.
13. What are the inflammatory markers of aging?
Neopterin, a product of immune cells, increases with healthy aging has been associated with age-related conditions such as Alzheimer’s. The white blood cells which secrete neopterin also produce inflammatory mediators connected with the chronic inflammation of aging. These mediators are known to increase C-reactive protein (CRP) which is also linked to aging.
14. What is the importance of the inflammatory markers associated with aging?
While there is no concrete evidence that inflammatory markers cause a shorter lifespan, indirect data support that these markers can be harmful.
· In a clinical trial of healthy volunteers, direct injection of recombinant CRP caused changes associated with the arteries and the endothelium, similar to those in the aging process.
· In vitro administration of CRP to endothelial cells resulted in a slowed reaction to vasoactive factors, resembling the endothelial hyporesponsiveness
15. Which inflammatory mediator’s effect can be reversed?
Research has shown that the damaged caused TNF-alpha, which restrains the growth of repair cells in the body, can be resolved with the use of antioxidant treatment.
16. How does the telomere shortening problem tie in with the concept of aging?
The quality of a cell to replicate itself is reduced as it divides, causing the cell to either age, die or become cancerous. During cell division, the ends of the chromosomes, “telomeres”, are not completely duplicated causing a gradual shortening in its length. This shortening will eventually trigger the release of cytokine IL-1 , an inflammatory response related to aging. It is also associated with ataxia, a disorder of premature aging. Yet another idea is that cell aging is thought to be a type of protective mechanism against cancer. So, in essence, as the body’s cells undergo continued division, the resulting new cells tend less functional leading to various problems discussed above.
17. What is the relationship between EPC and continued stress occurring within the endothelial wall?
The cell’s limited growth ability leads to a continual need for endothelial cell replacement from EPC. Since endothelial cells are constantly exposed to turbulent blood flow, mechanisms of repair and growth are needed. Supposedly, the more stress on a particular artery, the more cell division is required to compensate for cell loss. An example of this is seen in the iliac artery where telomeres are shorter due to a higher blood flow, when compared with the mammary artery which has a lower blood flow. Also, this validates the notion that age is associated with atherosclerosis.
· In a study, 100 patients with coronary artery disease and 25 control patients were examined. The telomere lengths were reduced in the EPCs of CAD patients. Medication used to lower cholesterol such as atorvastatin, were given to the CAD patients, which preserved telomere length by decreasing the amount of new EPC and oxidative stress, a precursor to telomere destruction.
· In a different analysis, smoking associated oxidative stress has been shown to stimulate stressed induced aging. However, other studies have identified inflammatory agents such as interferon gamma, TNF-alpha and oxidative mediators cause stress induced aging.
18. What is responsible for inhibiting EPC activity?
Recent studies have shown that an underlying inflammatory response for inhibiting EPC activity exists in degenerative diseases as well as in the normal aging process.
· Directly, inflammation suppresses the stem cell regeneration and EPC activity.
· Indirectly, inflammation places an increased demand on EPC due to the need for more EPCs.
19. How can inflammation response that inhibits EPC activity be reduced?
This form of inflammation can be reduced through dietary and medicinal measures such as the administration of TNF blockers, statin therapy, calorie restriction, exercise, consuming blueberries and green tea.
20. What are other therapeutic applications of EPC administration?
· In clinical studies, it has demonstrated that there is an overall increase in cardiac function and a reduction in tissue changes post injury after the administration of autologous bone marrow mononuclear cells. It was shown that EPC administration to injured myocardium triggered the production of new blood vessels to the injured myocardium. Additionally, studies involving other conditions of injury or fibrotic healing have shown decreased tissue damage and organ dysfunction.
· Another therapeutic approach involves directly placing EPC to the injured site. Normally, heart attack and stroke release EPC in response to injury. This phenomenon had researchers questioning whether mobilized EPC can be used as treatment.
21. What is the relationship between EPC and Granulocyte Colony Stimulating Factor (G-CSF)?
Over the years, G-CSF has been used clinically to mobilize hematopoietic stem cells (HSC) during donor stem cell harvesting. G-CSF is believed to cause changes in the bone marrow, including changes to the surrounding area. It also stimulates mobilization of EPC. To say that mobilized EPC has beneficial effects has yet to be fully understood.
· In a study with Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute Myocardial Infarction by Granulocyte Colony-Stimulating Factors (FIRSTLINE-AMI), 30 patients with ST-elevated heart attack were treated. Fifteen patients received six days of G-CSF, while the others received standardized care. Four months post injury, the group who received G-CSF developed a thicker myocardial wall at the injury site. Significant improvements in the heart’s pumping mechanism as well as a decrease in scarring of the heart muscle were seen.
· In a larger trial containing 114 patients, 56 were treated with G-CSF, which produced no significant results, partly due to the fact that mobilization of EPC was done immediately after the heart attack. In a different study, altered dosing showed improvement in angina.
· The most recent study demonstrated that in 41 patients with a large anterior wall AMI an improvement in the heart’s ability to eject blood from the left ventricle and a reduction in scar tissue was observed.
22. How can functional foods and nutraceuticals play a role in improving EPC levels?
The nutritional supplement Stem Rise contains a proprietary blend of yeasts, Goji berries, green tea extract and astragalus root extract, Ellagic acid from pomegranate extract and Beta 1, 3 glucan. In clinical trials, Stem Rise increased the number of circulating stem cells with even greater results after two weeks. An enhancement of stem cell mobility has been established to effectively fight disease, chronic ailments and strengthen cardiovascular health and wellness. It also protects these cells from normal wear and tear, and has been called a “powerful approach to anti-aging therapies.”
This summary was written in as simple of terms as possible, unfortunately in science and medicine descriptive words and/or terms may be unknown to a person that isn’t in this field. Virility Center doctors would be pleased to answer any questions.