Rapid and selective mobilization of specific stem cell types after consumption of a polyphenol-rich extract from sea buckthorn berries (Hippophae) in healthy human subjects.

PURPOSE: The aim of this study was to evaluate the effects of a proanthocyanidin-rich extract of sea buckthorn berry (SBB-PE) on the numbers of various types of adult stem cells in the blood circulation of healthy human subjects. STUDY DESIGN AND METHODS: A randomized, double-blind, placebo-controlled, cross-over trial was conducted in 12 healthy subjects. Blood samples were taken immediately before and at 1 and 2 hours after consuming either placebo or 500 mg SBB-PE. Whole blood was used for immunophenotyping and flow cytometry to quantify the numbers of CD45dim CD34+ CD309+ and CD45dim CD34+ CD309- stem cells, CD45- CD31+ CD309+ endothelial stem cells, and CD45- CD90+ mesenchymal stem cells. RESULTS: Consumption of SBB-PE was associated with a rapid and highly selective mobilization of CD45dim CD34+ CD309- progenitor stem cells, CD45- CD31+ CD309+ endothelial stem cells, and CD45- CD90+ lymphocytoid mesenchymal stem cells. In contrast, only minor effects were seen for CD45dim CD34+ CD309+ pluripotential stem cells. CONCLUSION: Consumption of SBB-PE resulted in selective mobilization of stem cell types involved in regenerative and reparative functions. These data may contribute to the understanding of the traditional uses of SBB for preventive health, regenerative health, and postponing the aging process.

Mobilization of bone marrow stem cells with StemEnhance improves muscle regeneration in cardiotoxin-induced muscle injury.

Bone marrow-derived stem cells have the ability to migrate to sites of tissue damage and participate in tissue regeneration. The number of circulating stem cells has been shown to be a key parameter in this process. Therefore, stimulating the mobilization of bone marrow stem cells may accelerate tissue regeneration in various animal models of injury. In this study we investigated the effect of the bone marrow stem cells mobilizer StemEnhance (SE), a water-soluble extract of the cyanophyta Aphanizomenon flos-aquae (AFA), on hematopoietic recovery after myeloablation as well as recovery from cardiotoxin-induced injury of the anterior tibialis muscle in mice. Control and SE-treated female mice were irradiated, and then transplanted with GFP(+) bone marrow stem cells and allowed to recover. Immediately after transplant, animals were gavaged daily with 300 mg/kg of SE in PBS or a PBS control. After hematopoietic recovery (23 days), mice were injected with cardiotoxin in the anterior tibialis muscle. Five weeks later, the anterior tibialis muscles were analyzed for incorporation of GFP(+) bone marrow-derived cells using fluorescence imaging. SE significantly enhanced recovery from cardiotoxin-injury. However, StemEnhance did not affect the growth of the animal and did not affect hematopoietic recovery after myeloablation, when compared to control. This study suggests that inducing mobilization of stem cells from the bone marrow is a strategy for muscle regeneration.

The stem cell mobilizer StemEnhance does not promote tumor growth in an orthotopic model of human breast cancer.

Bone marrow-derived stem cells (BMDSC) have been implicated in tumor formation, though it is not clear whether they contribute to tumor growth. A novel mobilizer of BMDSC (StemEnhance; SE) was used to investigate whether its daily administration promotes tumor growth. Forty mice were surgically transplanted with human MDA-MB-435-GFP breast cancer into the mammary fat pad of nude mice, The mice were gavaged for six weeks with 300 mg/kg of SE. Tumor growth was monitored using live whole-body fluorescence imaging. At the end of the study, tumors were excised and weighed. At the start of the feeding trial, tumor areas for both control and experimental group were statistically identical. Tumor growth rate was slower in the SE group (p = 0.014) when compared to the control group. After 6 weeks, tumor areas were 40% larger in the control p < 0.01) and mean tumor weight was 35% smaller in the SE-treated group (0.44 g vs. 0.68 g; p = 0.031). Feeding of SE did not promote tumor growth but rather reduced the growth of human MDA-MB-435 breast cancer.

Mobilization of human CD34+ CD133+ and CD34+ CD133(-) stem cells in vivo by consumption of an extract from Aphanizomenon flos-aquae--related to modulation of CXCR4 expression by an L-selectin ligand?

OBJECTIVE: The goal of this study was to evaluate effects on human stem cells in vitro and in vivo of an extract from the edible cyanobacterium Aphanizomenon flos-aquae (AFA) enriched for a novel ligand for human CD62L (L-selectin). EXPERIMENTAL APPROACH: Ligands for CD62L provide a mechanism for stem cell mobilization in conjunction with down-regulation of the CXCR4 chemokine receptor for stromal derived factor 1. Affinity immunoprecipitation was used to identify a novel ligand for CD62L from a water extract from AFA. The effects of AFA water extract on CD62L binding and CXCR4 expression was tested in vitro using human bone marrow CD34+ cells and the two progenitor cell lines, KG1a and K562. A double-blind randomized crossover study involving 12 healthy subjects evaluated the effects of consumption on stem cell mobilization in vivo. RESULTS: An AFA extract rich in the CD62L ligand reduced the fucoidan-mediated externalization of the CXCR4 chemokine receptor on bone marrow CD34+ cells by 30% and the CD62L+ CD34+ cell line KG1A by 50% but did not alter the CXCR4 expression levels on the CD34(-) cell line K562. A transient, 18% increase in numbers of circulating CD34+ stem cells maximized 1 hour after consumption (P<.0003). When 3 noncompliant volunteers were removed from analysis, the increase in CD34+ cells was 25% (P<.0001). CONCLUSION: AFA water extract contains a novel ligand for CD62L. It modulates CXCR4 expression on CD34+ bone marrow cells in vitro and triggers the mobilization of CD34+ CD133+ and CD34+ CD133(-) cells in vivo.

Natural killer cell activation and modulation of chemokine receptor profile in vitro by an extract from the cyanophyta Aphanizomenon flos-aquae.

The present research was designed to study the effects of an extract from the edible cyanophyta Aphanizomenon flos-aquae on human natural killer (NK) cells. We have previously shown, using a double-blind randomized placebo-controlled crossover design, that ingestion of 1.5 g of dried whole A. flos-aquae resulted in a transient reduction in peripheral blood NK cells in 21 healthy human volunteers, suggesting increased NK cell homing into tissue. We have now identified an extract from A. flos-aquae (AFAe) that directly activates NK cells in vitro and modulates the chemokine receptor profile. NK cell activation was evaluated by expression of CD25 and CD69 on CD3-CD56+ cells after 18 hours. Changes in CXCR3 and CXCR4 chemokine receptor expression after 5-60 minutes were evaluated by immunostaining and flow cytometry. AFAe induced the expression of CD69 on CD3-CD56+ NK cells, induced CD25 expression on 25% of these cells, and acted in synergy with interleukin 2. NK cells enriched by RosetteSep (StemCell Technologies Inc., Vancouver, BC, Canada) were not activated by AFAe, indicating that the NK activation was dependent on other cells such as monocytes. The low-molecular-weight fraction <5,000 of AFAe was responsible for the most robust NK cell activation, suggesting novel compounds different from previously reported macrophage-activating large polysaccharides.

The use of in situ bone marrow stem cells for the treatment of various degenerative diseases.

The potential for tissue repair and regeneration is encouraging in the light of novel research on the plasticity of adult stem cells. Intense research efforts over the last 3 years have provided solid evidence for the continuous generation of many types of tissue cells from adult stem cells as a normal part of our physiology throughout development and adult life in mammals, including humans. This opens new therapeutic avenues for many clinical problems and provides alternative opportunities at a time when much attention has been brought to the issue of using embryonic stem cells for research purposes and for the development of treatments for various diseases. Embryonic stem cells are pluripotent cells characterized by nearly unlimited self-renewal and differentiation capacity. However, evidence has accumulated over the past few years, indicating that adult bone marrow stem cells might have pluripotent properties similar to those of embryonic stem cells. Based on a review of the literature we propose the hypothesis that in situ mobilization of stem cells from the bone marrow and their migration to various tissues is a normal physiological process of regeneration and repair and that therapeutic benefits can be generated with less invasive regimens than the removal and re-injection of stem cells, through the stimulation of normal stem cell migration. We further propose that effort should be made to identify natural compounds characterized by their ability to augment this normal process of mobilization and re-colonization of bone marrow stem cells for the potential treatment of various degenerative diseases.

Pancreatic and intestinal enzyme activities in rats in response to balanced and unbalanced plant diets.

To simulate the effects of nutritionally adequate and inadequate vegetarian diets, rats were fed, for 28 days, an isonitrogenous, isocaloric, amino acid unbalanced cereal diet (CD) deficient in lysine and tryptophan or a balanced cereal-legume diet (CLD). The impact of these diets on enzymes responsible for digestion of proteins and carbohydrates were measured. Neither experimental diet significantly affected the animal's final weight or feed consumption in comparison with controls fed a standard mixed diet from plant and animal sources. However, during the first three weeks, the weight gain of rats fed the CD was significantly lower (p < 0.01; p < 0.05) than that of the controls. CD fed rats also had a higher feed efficiency ratio (p < 0.05), demonstrating increased feed consumption per unit of body weight. They also had decreased pancreatic alpha-amylase activity (p < 0.05), serum phytolytic and zoolytic alpha-amylase activity (p < 0.05) and serum protein level (p < 0.05) than the controls. Activity of pancreatic trypsin and intestinal enzymes (sucrase, maltase, aminopeptidase N) were the same as in the controls. In rats fed CLD, growth, food consumption, and enzyme activities did not change, however serum protein and glucose levels were higher (p < 0.025; p < 0.005) than in the controls. It is hypothesized that decrease in alpha-amylase activity was mostly related to the tryptophan deficiency in the CD because this enzyme contains the highest amount of tryptophan units among all tested enzymes.