Many different types of stem cells are being used in research and clinical practice globally.1 Examples include human embryonic stem cells (ESC), human cord blood or placental stem cells, adult stem cells (ASC), and even animal stem cells (live cell therapy). While there are clear advantages to using ESC due to their totipotential nature, their use in general therapeutics presents insurmountable moral problems.2,3 Although the use of human umbilical stem cells tends to overcome ethical problems, work in this field poses special technical challenges. These circumstances have led to major interest in the use of ASC. In ASC procedures, stem cells are harvested, grown, manipulated, and reintroduced. The overall objective of ASC treatments is to implant the cells, which are often coaxed down a pathway of differentiation toward a specific adult somatic cell type to replace diseased or ailing tissues.
ASC are pluripotent, and they have different degrees of versatility in their ability to engraft and replace damaged tissues. While some ASC appear limited in their ability to differentiate into various cell types, many recent studies show that such cells (especially stromal bone marrow or adipose tissue-derived) may have great versatility in some circumstances.1,4-22 Elegant biotechnology research is being undertaken to transform harvested ASC into highly specialized "functional" cell types for the potential treatment of disorders such as Parkinson's disease.1
There has been a great deal of high-quality research in the application of ASC treatments, especially in the field of human bone-marrow transplantation. However, there have been reports of poorly performed ASC treatments in offshore locations that are alleged to be ill equipped or devoid of important ancillary services to make the procedures safe and effective. Recent revisions to US laws that govern stem cell treatments (Obama legislation) have produced widespread interest in the development of stem cell treatment facilities, especially in centers of health-care excellence. While stem cell therapies are advancing meteorically, all current "classic" stem cell treatments provide a series of disadvantages or limitations.1
Innovative scientists have been working on the potential use of mobilized in situ ASC as a noninvasive form of stem cell treatment.23,24 This is the process of induction of adult stem cell recruitment (IASCR).25 A decade of research has led to current proposals that endogenous or in situ ASC (most notably bone-marrow stem cells) can be mobilized from their niches in the body, with the result that they may migrate to various organs and engage in tissue repair or regeneration.23-25 While this is somewhat futuristic, I have proposed that there may be several means whereby endogenous ASC could be released and promoted to differentiate into desired cell types to treat specific organ damage.25 This proposal is supported by major advances in the characterization compounds that can induce stem cell differentiation to specific cell types in vitro.1
The proposed noninvasive technology of IASCR has obvious advantages over the processes of harvesting and reintroduction of ASC. These processes form part of current complex treatment programs.1 A body of evidence has emerged showing that several pharmaceuticals or natural substances can mobilize ASC from human bone-marrow deposits, but some uncertainty surrounds the ability of mobilized ASC to home into damaged tissue and undertake a process of recruitment that will produce the desired treatment outcome of tissue repair or regeneration. However, diseased or damaged tissues provide complex signals to attract regenerative stem cells, and the body has a built-in homing system that it utilizes when ASC are part of an "internal repair kit."1,23-25 The development of IASCR represents a new horizon in stem cell treatments that could make stem cell therapies more portable and cost effective.25
The objective of this article is to highlight the ability of combinations of nutrients, botanicals, or herbals that can play a role in mobilizing ASC and their antioxidant protection during their migration. Earlier work is very important in the current proposals, and this research must be acknowledged and applauded.23,24 In IASCR, the R (for recruitment) assumes ASC recruitment, justified or otherwise. With further research, the R may stand for regeneration or repair of diseased or ailing tissues.
Adult Stem Cells at Work
Adult stem cells are ubiquitous in the body, and they live in "niches" in many organs. Most research has been performed with ASC of bone-marrow origin, where stem cells are encouraged to proliferate to support the presence of blood components, often following marrow ablation. It has been stated that the very presence of ASC in adults poses questions concerning the exact definition of a stem cell. While scientists have no problem in discussing the potential of several stem or progenitor cells to form new cell types or engage in tissue renewal, the concept of stemness emerges. In brief, stemness is the ability of a stem cell to produce different cell types and to self-renew.1
There is a large body of clinical and scientific literature that demonstrates the pluripotential of bone-marrow ASC. Bone-marrow ASC have been harvested and reinjected into patients, following varying degrees of laboratory manipulation, to treat the consequences of degenerative disease. Variable success is apparent in some anecdotal reports on the Internet (keywords: adult stem cells). The results of many of these studies are reported in animal experiments in great detail, but many human experiences remain quite anecdotal in their descriptions of clinical outcome.25 Bone-marrow ASC are engaged in the long-term replenishment of all blood elements, but they are composed of a group of nonhematopoietic ASC (stromal cells), which are precursors of bone, cartilage, and skeletal tissues.24,25 This limited view of ASC has been overturned by many observations of the ability of these ASC to form a much wider range of specific cell types that may play a pivotal role in tissue healing and cellular replacement or regeneration. In simple terms, ASC in a variety of niches in the body could migrate and translocate to a site of tissue damage where they may undergo cellular differentiation that improves organ structure and function.1,4-22
In their classic article in Medical Hypotheses (2002), Jensen and Drapeau describe a hypothesis to support some of the components of what I have termed IASCR.23 In brief, these scientists highlight the importance of the ability of ASC to target and grow at locations of tissue damage and an ability for this migration to occur after induced mobilization of ASC, most notably from bone-marrow. There are other steps to be applied to the concept of IASCR, which may include the use of agents to protect stem cells or improve their functionality and enhance their ability to differentiate into the desired types of adult somatic cells.25
Many authors confirm the pluripotent properties and ability of ASC to migrate within the body.1,4-25 Such studies include the ability of bone-marrow ASC to become functional myocytes, hepatocytes, osteocytes, and cells of the central nervous system.4-24 Available scientific information permits a clear conclusion that ASC have an ability to migrate from their tissues sites of origin and undergo cellular differentiation that results in a variable degree of repair of many different tissues.1
The laboratory identification of ASC involves a check for the presence of three characteristics that are hallmarks of stemness. First, the cells must be able to renew themselves; second, they must be able to differentiate into specific cell types; third, they must be transplantable with functional engraftment.1 A characteristic of all stem cells is the presence of telomerase, an important marker found in cancer cells. The presence of telomerase has led to proposals that many types of malignancies originate in stem cells, as a consequence of disorganized cell division.
The residual argument that promoting ASC activity in humans could lead to the development of cancer is not supported by current scientific knowledge or experimentation. At present, it appears to be a reasonable and safe proposal that ASC may be mobilized in the human body without significant adverse effects.25 The use of ASC technology has been perceived as widely acceptable in medical practice, because it rests on the relative safety and effectiveness of human bone-marrow transplantation, but regulatory issues concerning the use of ASC therapy in the US remain to be defined with clarity.1
Mobilizing Adult Stem Cells
Several drugs, biological agents, and nutritional factors exert effects on the mobilization and disposition of otherwise quiescent ASC (Table 1, p. 66). A number of nutritional cofactors exert effects on supporting the differentiation of stem cells (e.g., hematopoietic bone-marrow stem cells require vitamin D, B12, folic acid, and iron for maturation). Recent studies imply that single or combination formulations of natural substances may promote the mobilization of stem cells. Such natural agents include but may not be limited to carnosine, blueberries (and other anthocyanidin-containing botanicals), green tea derivatives, and components of algae (fucoidans and pigments; Table 1).23-25
Table 1: Factors that mobilize adult stem cells (ASC) or provide nutritional support, including antioxidant protection, for stem or progenitor cells. The effects of many agents on cell signaling cascades remain underexplored.
•Drugs (or isolated biologicals in clinical use or trials): IL1, IL3, IL6, Stem Cell Factor(s), erythropoietin, G-CSF, etc.
•Nutraceuticals: oleic acid, linolenic acid, blueberry, blue-green algae (AFA), green tea, fucoidan, and vitamin D3. Putative releasers or antioxidant protection may occur with fucoxanthin, beet root, spirulina, spinach, Ashwagandha, grape seed extract. Cofactors: vitamin B12, folate, etc.
In conventional medical practice, a number of drugs have been utilized to stimulate bone-marrow stem cell activity (e.g., granulocyte-macrophage colony-stimulating factor [GM-CSF], erythropoietin).26,27 In addition, various combinations of cytokines can facilitate the growth of stem cells in vitro (e.g., IL-1, IL-3, IL-6, erythropoietin, and Stem Cell Factor[s]). In vitro comparisons of specific synergistic formulae of putative stem cell supporting nutrients with the actions of the drug GM-CSF imply that such combinations of nutrients may in some circumstances increase bone-marrow stem cell proliferation to a degree greater than GM-CSF.24 Whether mobilized ASC can be recruited consistently and result in engraftment to replace diseased or ailing tissues requires further investigation; and this subject has attracted legal controversies with regulatory authorities or "bounty hunters" who affect the sale of dietary supplements.28,29
There have been many anecdotal reports of benefit following the use of nutritional agents to support ASC structure and function, but these reports are largely in testimonial format, often displayed on the Internet in multilevel marketing information (network selling). However, it is recognized that ASC are often "tissue specific" in their homing characteristics.1,17,19,22-24 Moreover, diseased or degenerating cells produce a variety of chemical messengers (e.g., cytokines) or have alterations of cell surface receptors that may attract reparative ASC.1,17,19 A key but sometimes overlooked factor in all ASC technology is protection of the utilized stem cells (in situ or exogenous allograft administration) from oxidative stress by the use of redox balanced antioxidants. Such antioxidants may be present in several nutritional factors that promote stem cell structure and function (e.g., fucoxanthin in fucoidan-containing brown algae).25,30
Key Contemporary Research
Several scientists have presented experimental or clinical information on the use of specific nutrients or botanicals for the mobilization of ASC.23-25 There has been considerable examination and controversy concerning the use of Aphanizomenon flos-aquae (AFA, or blue-green algae) for use as an enhancer of stem cell mobilization, among other things. In February 2003, a California court ruled that many statements used in the marketing of a branded form of AFA were deceptive. The court ruled that the use of this ingredient was associated with a series of advertising claims that were untrue, unfounded, or likely to mislead, to variable degrees.28,29 However, more recent research would seem to imply that there is a scientific basis for the use of AFA in the nutritional support of stem cell mobilization.31
In well-conducted experiments, preparations of AFA containing a novel cyanobacterial ligand for human L-selectin were shown to have an important role in stem cell biology. An extract of AFA enriched for a novel ligand for human L-selectin was studied in laboratory and human experiments. L-selectin is an example of a cell-adhesion molecule that plays a role in the retention and mobilization of bone-marrow stem cells into the systemic circulation. In brief, scientists showed that oral administration of this extract of AFA contained an L-selectin blocker that promotes the release of stem cells from the bone marrow by interfering with the functions of CXCR4 cemokine receptors that are specific for stromal derived factor-1 (SDF-1).31
Any compound that interferes with CXCR4 or SDF-1 will promote stem cell mobilization. These experiments involving the administration of the AFA extract resulted in a 25% increase in the number of circulating stem cells at one hour postadministration, in humans, compared with placebo. Stem cells were measured in blood samples by defining the presence of the CD34+ cell. These results were found to be reproducible in humans. The scientists commented that the mobilization of stem cells treated by an L-selectin blocker appears to be of a lower magnitude and greater transience of effects than can be achieved by the administration of granulocyte colony-stimulating factor (G-CSF). In separate experiments, scientists have proposed that an enhanced level of circulating CD34+ stem cells a reasonable indicator of good health.31
Several nutrients appear to have an effect on mobilizing bone-marrow ASC or stromal cells. For example, vitamin D and 1,25-dihydroxyvitamin D3 are modulators of several immune functions, including an ability to stimulate the production of progenitor cells.32 In addition, oleic and linoleic acids have been shown to promote the proliferation of intestinal stem cells and hematopoietic precursor cells, respectively.33,34 Combinations of these simple nutrients form a significant component of any product used for stem cell support; and they are likely to act safely and synergistically with specific ASC-mobilizers, such as AFA.25 The power of synergy in the use of combinations of nutrients and botanicals has been highlighted in recent studies by Bickford et al. (2006).24 In one important study, they undertook laboratory (in vitro) studies to examine the ability of certain natural substances (nutraceuticals) to work synergistically to promote the proliferation of human ASC.
In these studies, the scientists directed their attention to hematopoietic (bone-marrow) stem cells, with the knowledge that these types of ASC are used routinely in the relatively common practice of human bone-marrow transplantation. These studies show that certain nutrients or botanical extracts were able to stimulate bone-marrow cell proliferation in a manner that was dose-dependent; that is, related to the amount of the administered natural substances.24
The experiments by Bickford et al. were performed using a positive control substance known to stimulate bone-marrow stem cell activity. The positive control substance used in these experiments was GM-CSF. This pharmaceutical is often prescribed routinely to counteract side effects of toxic drugs used in cancer treatments.26 Chemotherapeutic drugs often result in bone-marrow damage and suppression of immune function.
By using GM-CSF as a control, the scientists could make laboratory assessments of the ability of various combinations of nutraceuticals (nutrients or botanicals) to induce positive effects on the stimulation and mobilization of bone-marrow stem cells.24 The positive control, using GM-CSF, resulted in an anticipated stimulation of bone-marrow cell production by a factor of about 46%.24 While this ability to stimulate bone-marrow cell proliferation was more substantial than the use of any single nutrient or natural substance under investigation, the combined use of natural substances (nutraceuticals) resulted in a greater increase in bone-marrow cell proliferation than was observed with GM-CSF.24 In other words, in these experiments, combinations of nutrients and botanicals (natural agents) worked better than the control drug GM-CSF.24
It is relevant to note that several nutraceuticals that promote ASC production have a benefit of antioxidant actions that may help prevent damaged or circulating ASC from oxidative stress (free-radical generation). Oxidative stress can attack the viability and impair the potentially beneficial functions of "stimulated" or "mobilized" ASC.25
It is quite valuable to examine in detail just how powerful the synergistic effects of nutrient and botanical combinations actually are on bone-marrow cell proliferation. Bickford et al. showed that a combination of blueberry and green tea extracts caused specific types of bone-marrow cell proliferation by a factor of up to 70%; and a simple combination of blueberry extract with vitamin D3 caused an increase of about 62%. When blueberry extract was combined with carnosine, an increase in proliferation of bone-marrow cells was observed to be about 83%.24
The experiments of Bickford et al. were further extended to the study of various natural substances (nutraceuticals) on the stimulation of stem cells in the bone marrow.24 ASC can be identified and segregated by identification of surface antigens (laboratory markers). A good example of the presence of such surface antigens is the identification of CD133+ or CD34+ antigen-receptor expressions. In the experiments, the drug GM-CSF increased CD34+ and CD133+ (early stem cells) by a factor of about 48%, but a combination of the natural substances carnosine, blueberry extract, green tea extract, and vitamin D3 was potent.24 This combination increased the early stem cells by a factor of 68%.24 It is gratifying to see how synergistic combinations of natural substances (with no significant adverse effects) can sometimes outperform expensive prescription drugs, such as GM-CSF, in this context.
The use of seaweed in stimulating stem cell production has been ascribed to the ability of complex carbohydrates (fucoidans), contained within seaweed, to promote ASC release from bone-marrow stores into the peripheral blood or general circulation.36-39 While fucoidans may bind with fibroblast growth factors and promote angiogenesis (new blood vessel growth), they have immunomodulating, anti-inflammatory properties.36-39 Angiogenesis has been highlighted as an important process in human stem cell engraftment.1
Chris D. Meletis, ND, has drawn attention to the stem cell enhancement potential of fucoidan found in marine algae.36 This polysaccharide compound, found in abundance in wakame seaweed, has been shown to exert influence on the mobilization of endothelial progenitor cells, associated with the incorporation of such cells into ischemic tissue. It would appear that fucoidan acts through the modulation of the activity of SDF-1. In addition, it appears that fucoidan has proangiogenic activity which is very important in the repair of tissue damage.36-39 The benefits of fucoidan appear to be particularly important in general tissue repair processes and cardiovascular health.
In brief, it appears that there is a group of miscellaneous botanical agents that may have value in induction of ASC mobilization or recruitment. Examples include green tea polyphenols, blueberries, other anthocyanidins and vegetables including spirulina, spinach, grape seed extract, and Ashwagandha.40,41,25 There are many potential mechanisms whereby these botanicals can exert benefit in IASCR. For example, green tea polyphenols have anti-aging, angiogenic, anticancer, and cell-protective benefits. Blueberries, spinach, and strawberries contain compounds that modulate cell-signaling cascades.42 They have regenerative effects on certain cell populations.42 Other botanicals that have been mentioned will provide, at least, antioxidant and variable cell regulatory potential.25
While it is recognized that ASC are often "tissue specific," they may be somewhat limited by an ability to replace specific cell types that are damaged. However, ASC retain a degree of pluripotency (multipotent) that permits them to differentiate (form a special adult cell identity) into somatic cell types that are present in different organ tissues. Clearly, further investigations of the ability of nutraceuticals to support ASC proliferation and mobilization are required.25
Summarizing the Concepts of IASCR
Table 2 simplifies the concepts proposed for the use of IASCR.25
Table 2: The Concepts of How to Utilize the Induction of Adult Stem Cell Recruitment (IASCR)
•Mobilize ASC from bone marrow and other niche locations.
•Increase circulation of ASC with semicontinuous, safe stimuli. (Herbs, botanicals and nutrients are preferred to drug approaches: they cost less and have fewer side effects.)
•Protect ASC from oxidative damage.
•Encourage homing to desired target organ(?)
•In vivo assistance in the differentiation of ASC to replace cell types of the diseased organ has to be developed (the "human petri dish" approach).
•A body of research demonstrates that human bone-marrow ASC are able to "home in" on diseased organs and differentiate into many cell types.
There are several unresolved issues in my above proposals concerning IASCR. While it seems clear that ASC release and migration occur following the use of several nutraceuticals, the question of deployment of mobilized ASC to organs has not been evaluated. Diseased or ailing tissues are known to produce many chemoattractants for circulating stem cells.17-19 Intrinsic in the progress of IASCR following stem cell mobilization is a plausible proposal that homing of progenitor or ASC will occur in a reproducible manner. Questions arise concerning the engagement and recruitment of ASC at target sites. This process must be followed ideally by desired proliferation and engraftment. These matters remain to be clarified.
Within the concepts of IASCR rest the possible applications of some substances that can help promote the in vitro differentiation of mobilized stem cells towards desired cell types, in order to regenerate specific disease organs. Many physical or chemical manipulations are applied in the laboratory to transform (manipulate) harvested stem cells, in order that they may be stimulated to differentiate along certain cell lineages. Perhaps these "petri dish" manipulations of stem cells can be applied in an overall process of IASCR, making the circumstances somewhat like a "human petri dish" of stem cell differentiation? These matters are quite speculative at present, but it is known that the simple application of key nutrients can have major effects on pathways of differentiation taken by cultured stem cells in vitro.1
To use nutraceutical induction of ASC mobilization or recruitment (IASCR), one must propose a rational basis for this novel procedure. The nutraceuticals that have been shown to have mobilization and protection potential for ASC have potential health benefits that extend beyond the act of IASCR, including their antioxidant potential and cell-regulatory potentials. While I acknowledge that much further research may be required to validate my proposals for the routine use of IASCR, cumulative evidence to date reinforces this promising novel approach for disease management and, perhaps, the promotion of longevity.25
Formulations for Stem Cell Support
In this overview, the power of synergy among nutrients, herbals, and botanicals in the facilitation and mobilization of ASC and their potential recruitment by damaged or ailing tissues has become apparent. It seems prudent to conclude that the use of a single stem cell mobilizing factors alone, for example, AFA, is not likely to be as effective as synergistic combinations of nutraceuticals. These circumstances make several proposals on single or limited combinations of nutrients with botanicals somewhat obsolete. Cumulative scientific studies appear to support the use of more complex synergistic nutraceutical formulations, with greater potential functionality. These proposals supersede several existing patents on stem cell mobilization. Table 3 proposes a complex nutraceutical formulation that can be used in the support of stem cells.
Table 3: One of Several Proposals for Complex Synergistic Formulations to Induce Adult Stem Cell Mobilization and Antioxidant Protection, with Ancillary Functionality
(Courtesy of Holt MD Technologies, www.naturalclinician.com)
•fatty acids: linolenic and oleic acid
•antioxidant protectors, including anthocyanidins (blueberry and beet root), spirulina, green tea polyphenols, OPC, and fucoxanthin
•key nutrient support with vitamin D3 for cell proliferation and nutritional support of bone-marrow function with vitamin B12 and folate
•specific evidence-based stem cell releasers; e.g., AFA, blueberry, vitamin D3, and fucoidan
More than a decade of research exists in the use of natural compounds to help mobilize or recruit endogenous ASC. I propose the concept of IASCR with the use of nutritional support for stem cell function.25 This approach appears feasible and readily applicable without any significant risks of adverse effects. This noninvasive area of stem cell technologies appears quite attractive, given the lack of portability and the limitations of current stem cell procedures that require a combination of advanced clinical skills and sophisticated laboratory support.
Stephen Holt, MD PhD, DSc, LLD (Hon.) DNM, ChB, FRCP (C), MRCP (UK), FACP, FACG, FACN, FACAM, KSJ, Distinguished Professor of Medicine (Emerite), scientific advisor, Natural Clinician LLC, is a best-selling author, award-winning medical teacher, researcher, and clinician. He has published several hundred articles in peer-reviewed medical literature and more than 20 books. Dr. Holt has recently been distinguished by his inclusion in the academy's Who's Who in Anti-Aging and Regenerative Medicine.
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