eCAM Advance Access originally published online on May 4, 2006
eCAM 2006 3(2):167-169; doi:10.1093/ecam/nel023
© The Author (2006). Published by Oxford University Press. All rights reserved
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Stem Cells and CAM
Edwin L. Cooper
Laboratory of Comparative Neuroimmunology, Department of Neurobiology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California 90095-1763, USA
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Stem Cells, Regenerative Medicine and Evolution
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It is no exaggeration that stem cells are a hot topic in the
international biomedical arena. In California we are particularly
and actually aware of this fact. We started the new year on
January 12 with a Stem Cell Technology Conference focusing on
senescence. More than a year after California voters elected
to give $3 billion in bonds to fund stem cell research, and
with the measure stalled in legal proceedings, professors and
researchers met to discuss the proposition and other related
concerns at UCLA for a stem cell symposium February 5, 2006
(
1). At this event, called ‘Stem Cells: Promise and Peril
in Regenerative Medicine’, several stem cell research
experts discussed various topics, all with the goal of illuminating
the complex problems of Proposition 71 and its implications.
The symposium was organized by the UCLA Center for Society and
Genetics, the UCLA Institute for Stem Cell Biology and Medicine
and the UCLA School of Law.
Six days later, there was a similar event: the UCLA 10th Annual Health Care Symposium. One of the four speakers was Irving Weissman, MD, director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine. For those interested in evolution, Weissman has devoted a good portion of his career to understanding the origins of stem cells in colonial tunicates (2). Then just under a month later, on March 3, there was another 1-day symposium: ‘Stem Cells, Pathways and Cancer: From Biology to Therapy’. The two main topics covered aspects of cancer stem cell biology, models and disease and of cancer stem cell pathways as therapeutic targets.
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Stem Cells on CAM: Ears and Teeth on the CAM
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CAM, of course, in the context of
eCAM means complementary and
alternative medicine. But for the purpose of this editorial,
let us engage in a bit of fancy and make a play on words, so
that CAM can also mean chorioallantoic membrane. Thinking of
CAM in this way conjures up several meanings: (i) stem cells
and embryonic development
per se; (ii) stem cells and post-embryonic
development (i.e. can stem cells rejuvenate or regenerate lost
organs, post-embryo, in the adult?); (iii) CAM and stem cells.
The first point relates to my masters thesis, in which I isolated
the embryonic chick otocysts (the ear primordium of 4-day-old
chick embryos) and implanted them on the CAM of older embryos
(
3). The most difficult part of the experiment was to isolate
this tiny primordium under sterile conditions and drop it onto
the CAM, a highly vascularized extra-embryonic membrane. Virtually
any group of cells, tissues or organs can be readily vascularized
and continue to differentiate and develop or, in the case of
fully developed structures, enjoy a brief period of maintenance
by the blood vessels of the CAM. Of course, the host chick continues
its development, making it essential to do serial transfers
or, in the case of my embryonic ear, stop the process, open
the egg and find a fully differentiated ear with semicircular
canals and branches of the two nerves that innervate it. Later,
still imbued with a high level of excitement, I suggested the
technique to my dear friend Harold C. Slavkin, dean of the USC
School of Dentistry. He tried the same procedure with tooth
primordia and, of course, achieved a high level of differentiation
(
4).
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Stem Cells and Limb Regeneration
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Still fascinated by multipotent stem cells and what they could
do in the right environment, I embarked on a potential PhD thesis
at Brown University (1959–63). Pursuing my research with
the late Professor R.J. Goss, I learned about the unique regenerative
capacities of some urodeles or tailed amphibians (salamanders)
capable of regenerating almost any component of their body (
5).
It has been known for several hundred years that if a salamander's
limb is removed, amazing events occur that consist of wound
healing and the gradual emergence/appearance of the blastema,
a mound or nubbin of stem cells that can re-differentiate and
regenerate or refurbish or replace seemingly
de novo: new epidermis,
connective tissue, muscle, cartilage, bone. I wanted to grow
that multipotential blastema, that universal precursor in tissue
culture, to see whether I could obtain, in effect, components
of the limb. What a feat (
6)! With much sorrow, I obtained only
minimal but tempting results, a bit of cartilage here and there,
just enough to keep me pushing harder to get what I thought
would be a limb in culture.
Alas, as a graduate student of only 23 years of age, with no experience in culturing ectothermic vertebrate tissues, there were problems. Evolution and ontogeny were ready for this innovation, as echoed by the reigning stalwarts of developmental biology—notably the late Professor Paul Weiss of Rockefeller University, who strongly encouraged me to tackle the problem (7). Imagine the basic information and understanding we could gain if we were able to cultivate that mound of salamander blastemal cells in and/or around damaged spinal cord of salamanders. Is this not an approach worth trying? Because of the totipotentiality of these cells, it seems reasonable that we could use this salamander system as a model for understanding how adult stem cells may function when confronted with a situation requiring regeneration or replacement or repair of a lost part, either naturally or by means of experimentation. What I tried to do is still relevant and actively pursued in salamanders, i.e. deriving the blastema from regenerating salamander limbs and analysis in vitro (8,9).
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CAM and Mammalian Stem Cells
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Now, I would like to consider just a few examples that may be
a little more pertinent to
eCAM, especially in our search for
natural products and their effects on stem cells. Roscetti
et al. (
10) have examined the influence of a methanolic extract
of
Hypericum perforatum L. and of purified hypericin, which
have been comparatively tested on the growth of a human erythroleukemic
cell line (K562). This work confirms the interesting role of
H. perforatum L. in cancer therapy and strongly supports the
hypothesis that agents other than hypericin present in the total
extract, acting separately or in a combined manner, can impair
tumor cell growth. Ferraz
et al. (
11) screened crude methanolic
extracts of six species of
Hypericum growing in southern Brazil
(
Hypericum caprifoliatum Cham. & Schlecht.,
Hypericum carinatum Griseb.,
Hypericum connatum Lam.,
Hypericum myrianthum Cham.
& Schlecht.,
Hypericum polyanthemum Klotzsch ex Reichardt
and
Hypericum ternum A. St. Hil.) for their antiproliferative
activity against two cell lines (HT-29 human colon carcinoma
cells and H-460 non–small cell lung carcinoma). The most
active fractions were the hexane fractions obtained from
H. caprifoliatum,
H. myrianthum and
H. ternum. Using another product,
Gao
et al. (
12) found that
G. psilostachys ethanolic extract
inhibits the proliferation of K562 cells and disrupts the normal
dynamic of microtubules during mitosis.
Turning to the nervous system, Hostanska et al. (13) have reported the ability of HP and of polyphenolic procyanidin B2 (PB-2) to inhibit the growth of leukemia K562 and U937 cells, brain glioblastoma cells LN229 and normal human astrocytes. Cytocidal effects of HP and its synergistic cooperation with HY in tumor growth inhibition make the St John's wort an interesting option in cancer warranting further in vitro and in vivo investigation. Finally, Bouhon et al. (14) have examined neural differentiation mouse in embryonic stem cells in chemically defined medium. Neural differentiation in CDM did not occur by a simple default mechanism but was dependent on endogenous FGF signaling, and it could be blocked by adding BMP4 and LiCl to simulate WNT activation. Neural differentiation was also inhibited by antagonizing endogenous hedgehog activity. Taken together, the profile of gene expression changes seen in CDM cultures recapitulates those seen in the early embryo and is suggestive of common developmental mechanisms.
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CAM or CAM?
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So now let us put together the first CAM (chorioallantoic membrane
of chick embryos, a place where stem cells can thrive and differentiate)
and the blastemal cells (stem cells of adult salamanders) and
the newer CAM and stem cells. What is there? Are there opportunities
for meshing the two CAMs and stem cells? Or has this been an
enthusiastic and joyous reminiscence and an easy play on words?
Actually, to mention a few examples,
eCAM has already been at
the forefront in terms of stem cells from the viewpoint of evolution
and primitive cells (
15,
16), modulatory effects of certain plants
(
17,
18), natural health products (
19) and herbs and hemopoietic
stem cells (
20).
According to Ventura (21),
evidence-based medicine is switching from the analysis of single diseases at a time toward an integrated assessment of a diseased person. Complementary and alternative medicine (CAM) offers multiple holistic approaches, including osteopathy, homeopathy, chiropractic, acupuncture, herbal and energy medicine and meditation, all potentially impacting on major human diseases. It is now becoming evident that acupuncture can modify the expression of different endorphin genes and the expression of genes encoding for crucial transcription factors in cellular homeostasis. Extremely low frequency magnetic fields have been found to prime the commitment to a myocardial lineage in mouse embryonic stem cells, suggesting that magnetic energy may direct stem cell differentiation into specific cellular phenotypes without the aid of gene transfer technologies. This finding may pave the way to novel approaches in tissue engineering and regeneration. Different ginseng extracts have been shown to modulate growth and differentiation in pluripotent cells and to exert wound-healing and antitumor effects through opposing activities on the vascular system, prompting the hypothesis that ancient compounds may be the target for new logics in cell therapy. These observations and the subtle entanglement among different CAM systems suggest that CAM modalities may deeply affect both the signaling and transcriptional level of cellular homeostasis. Such a perception holds promises for a new era in CAM, prompting reproducible documentation of biological responses to CAM-related strategies and compounds. To this end, functional genomics and proteomics and the comprehension of the cell signaling networks may substantially contribute to the development of a molecular evidence-based CAM.
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Footnotes |
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For reprints and all correspondence: Edwin L. Cooper, Distinguished Professor, Laboratory of Comparative Neuroimmunology, Department of Neurobiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California 90095-1763, USA. Tel: +1-310-825-9567; Fax: +1-310-825-2224; E-mail:
ecam{at}mednet.ucla.edu
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References
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- Tseng W and Taylor S. Delving into stem cells UCLA Daily Bruin February 6, 2005
- Laird DJ, De Tomaso AW, Weissman IL. Stem cells are units of natural selection in a colonial ascidian Cell 2005; 123: 1351–60 Erratum in: Cell 2006;124:647–8[CrossRef][Web of Science][Medline]
- Cooper EL. Differentiation of the chick otocyst on the chorioallantoic membrane Atlanta University MS Thesis, 1959
- Slavkin HC and Bavetta LA. Odontogenesis in vivo and in xenografts on chick chorioallantois—I Arch Oral Biol 1968; 13: 145–54[CrossRef][Medline]
- Goss RJ. Adaptive Growth 1964;London Logos Press Ltd
- Cooper EL. Culture of the regeneration blastema from salamanders 1959; Brown University
- Weiss P. Principles of Development 1939;New York Henry Holt and Co
- Prince DJ and Carlone RL. Retinoic acid involvement in the reciprocal neurotrophic interactions between newt spinal cord and limb blastemas in vitro Brain Res Dev Brain Res 2003; 140: 67–73[CrossRef][Medline]
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- Roscetti G, Franzese O, Comandini A, Bonmassar E. Cytotoxic activity of Hypericum perforatum L. on K562 erythroleukemic cells: differential effects between methanolic extract and hypericin Phytother Res 2004; 18: 66–72[Medline]
- Ferraz A, Faria DH, Benneti MN, da Rocha AB, Schwartsmann G, Henriques A. von Poser GL. Screening for antiproliferative activity of six southern Brazilian species of Hypericum Phytomedicine 2005; 12: 112–5[Medline]
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- Hajtó T, Hostanska K, Berki T, Pálinkás L, Boldizsár L, Németh P. Oncopharmacological perspectives of a plant lectin (Viscum album agglutinin-I): overview of recent results from in vitro experiments and in vivo animal models, and their possible relevance for clinical applications Evid Based Complement Altern Med 2005; 2: 59–67[CrossRef]
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