**11. Stem cells**

Stem cells are specific cells with ability to unlimited divisions and differentiation. There are many types of stem cells depending on the differentiation degree. Residual small cells with embryonic stem cells phenotype (*VSELs, Very Small Embryonic-like Cells*) are a population of pluripotent cells deposited in developing organs during embryogenesis. In the bone marrow VSELs find beneficial conditions to growth and become reserve cell line participating in tissue and organ regeneration. In the postnatal life they are inactive and flow in blood stream in small amount. Mobilization of VSEL's is considered as a part of stress response it can increase upon different impulses e.g. tissue damage, ischemia, hypoxia, myocardial infarction, open heart surgery, extracorporeal circulation. Cells mobilized from bone marrow penetrate to blood and are attracted to damaged tissues by chemotactic factors, e.g. SDF-l, HGF/SF, or VSEGF.

10 Neuroendocrinology and Behavior

events and adjustment of treatment (3).

**Figure 1.** Natruretic factors interactions.

**11. Stem cells** 

responses are aimed at maintaining adequate vital organ perfusion but can lead to unfavorable and undesirable changes both in the heart and the vascular system. An impaired regulation of cardiac autonomic system and activation of many neurohormonal factors as well as the rennin-angiotensin-aldosterone system (RAAS). These changes may contribute to numerous early and late complications e.g. dysregulation of fluid homeostasis, effusions, detrimental remodeling, protein-losing enteropathy and limited exercise capacity. They can also serve as important indices for risk stratification, prediction of unfavorable

Stem cells are specific cells with ability to unlimited divisions and differentiation. There are many types of stem cells depending on the differentiation degree. Residual small cells with embryonic stem cells phenotype (*VSELs, Very Small Embryonic-like Cells*) are a population of pluripotent cells deposited in developing organs during embryogenesis. In the bone marrow

**LAP**

Researches who identified and described morphology of VSELs also showed the ability of those cells to proliferate and differentiate into all three primary germ layers in appropriate differentiating medium. It has been also proved that VSELs express many markers of primordial germ cells, e.g. fetal alkaline phosphatase, Oct-4, SSEA-l, CXCR4, Mvh, Stella, Fragilis, Nobox and Hdac6, indicating their similarity to germ cells through which genes are passed from generation to generation – the best reservoir of stem cells (7, 8). Most active translocation of stem cells takes place during early stage of human embryogenesis. In the beginning of gastrulation and organogenesis stem cells migrate to places of new tissues and organs formation. Subsequently, stem cells settle down in tissue specific spaces and constitute a cell line undergoing self-renewal process. These cells also replenish damaged or apoptotic cells during individual life. VSELs may accumulate in bone marrow under the influence of chemotactic factors (correlation between CXCR4 receptor and lymphokine SDF-1). After colonizing bone marrow VSELs find beneficial conditions to growth and become reserve cell line participating in tissue and organ regeneration. In normal conditions VSELs circulate in the peripheral blood in small number and can increase upon different stimuli e.g. tissue damage or severe stress (ischemia, hypoxia, myocardial infarction, open heart surgery, extracorporeal circulation) (9). Cells mobilized from bone marrow penetrate to blood and are attracted to damaged tissues by chemotactic factors, e.g. SDF-l, HGF/SF, or VSEGF. It has been proved that many clinical scenarios are associated with increase of stem cells in bloodstream. Increase of the number of bone marrow derived stem cells was observed in skeletal muscle injury, myocardial infarction, stroke, bones fractures, leasions of the liver and kidneys, ischaemia of the extremities and after lung or liver transplantation. These cells were described as endothelial progenitor cells (EPC), myocardial or muscle progenitor cells, neural progenitor cells, liver progenitor cells etc… These data indicate that during injury of the tissues and organs non-hematopoetic stem cells are mobilized from the marrow (10) and probably from other tissue niches to the blood where they circulate as a source of the stem cells supporting regeneration of the tissues (11, 12). This process is governed by injured tissue derived chemoattractants such as SDF-l, and other factors e.g.: VEGF, HGF/SF, UF and FGF-2. It is also known that transcriptional factor HIF-1 (hypoxia regulated/induced transcription factor) connected with the tissue ischemia takes important palce in regulation of expression of these factors. The promotor for sdf-l, vegf and hgf/sf gens have bounding places for HIF-1. Therefore hypoxia / cyanosis can induce expression of factors responsible for stem cells releasing and their migration to the injured tissues and organs. VSELs which are present in the marrow are quiescent and they need unknown factors for activation and stimulation of their activity. These incentives and modulators are unknown.

Recent research indicates that in the mature hearts of the mammalians there is a population of the cells capable of mitotic divisions named cardiac stem cells (CSC). They are pluripotential, clonogenic, and self-replicable. Their location in the herat seems to be related to the mechanical load of given segment of the heart muscle and is inversely proportional to hemodynamic load. The number of CSC depends on the methodology of counting and ranges from 1/8000 to 1/20 000 cardiomyocytes or 1/ 32 000 – 1/80 000 all cells of the heart.

Neuroendocrine Regulation of Stress Response in Clinical Models 13

pattern of pulsatile release of these hormones characterize the prolonged phase of critical illness. Cortisol levels remain elevated in chronic critical illness despite a decrease in ACTH release. The metabolic result of this neuroendocrine array is worsen metabolism of fatty acids and a propensity for fat storing and protein wasting. The immune effects related to neuroendocrine disturbances are impaired lymphocyte and monocyte function and increased lymphocyte apoptosis. It leads to catabolic state and multiple organ dysfunction. Duration of immune suppression correlates strongly with the incidence of related infection. Tissue damage and strong stressors (such as cyanosis, circulatory insufficiency) stimulate

regenerative and reparative processes involving stem cells.

**Figure 3.** Very small embryonic-like cells extracted from the heart

*Department of Pediatric Cardiac Surgery, Polish - American Children's Hospital,* 

This work is supportet by government grant No 2011/01/B/NZ5/04246

nerve. Br J Anaesth. 2009 Apr;102(4):453-62.

[1] Chesnokova V, Melmed S. Endocrinology. Neuro-immuno-endocrine modulation of the hypothalamic-pituitary-adrenal (HPA) axis by gp130 signaling molecules. 2002

[2] Johnston GR, Webster NR Cytokines and the immunomodulatory function of the vagus

[3] Francis DP, Shamim W, Davies LC, Piepoli MF, Ponikowski P, Anker SD, Coats AJ. Cardiopulmonary exercise testing for prognosis in chronic heart failure: continuous and independent prognostic value from VE/VCO(2)slope and peak VO(2). Eur Heart J

[4] Arena R, Humphrey R. Comparison of ventilatory expired gas parameters used to predict hospitalization in patients with heart failure. Am Heart J 2002;143:427–432.

**Author details** 

**Acknowledgement** 

May;143(5):1571-4.

2000;21:154–161.

**12. References** 

*Jagiellonian University, Krakow, Poland* 

Jacek Kolcz

**Figure 2.** Flow cytometry – mobilization of VSELs in children undergoing heart surgery due to congenital heart diseases

In population of our patients we've obtained blood specimens before the operation and during the hospitalization to determine the level of VSELs mobilization. Using the flow cytometry it has been shown that VSELs appears in peripheral blood with a specified pattern of mobilization during surgery and directly after it (Fig.2.) and confirmed the presence of those cells within myocardium Fig.3.

The acute phase of stress response is characterized by increased release of neuroendocrine mediators from the hypothalamus and pituitary. This is aimed on the blood pressure maintenance and mobilization of fuel substrates at the expense of deregulation of homeostatic mechanisms, immunologic response, growth, development and regeneration. If stress response is insufficient to maintain tissue perfusion, shock appears.

During the prolonged phase of critical illness, the effects of the stress response mediators, may be harmful. Decreased levels of anterior pituitary hormones and loss of the normal pattern of pulsatile release of these hormones characterize the prolonged phase of critical illness. Cortisol levels remain elevated in chronic critical illness despite a decrease in ACTH release. The metabolic result of this neuroendocrine array is worsen metabolism of fatty acids and a propensity for fat storing and protein wasting. The immune effects related to neuroendocrine disturbances are impaired lymphocyte and monocyte function and increased lymphocyte apoptosis. It leads to catabolic state and multiple organ dysfunction. Duration of immune suppression correlates strongly with the incidence of related infection. Tissue damage and strong stressors (such as cyanosis, circulatory insufficiency) stimulate regenerative and reparative processes involving stem cells.

**Figure 3.** Very small embryonic-like cells extracted from the heart
