Author and Reporter: Ritu Saxena, Ph.D.
Introduction
Blood vessels arise from endothelial precursors that are thin, flat cells lining the inside of blood vessels forming a monolayer throughout the circulatory system. ECs are defined by specific cell surface markers including CD31, CD34, CD105, VE-cadherin, vascular endothelial growth factor receptor 1 [VEGFR-1], VEGFR-2, Tie-1, Tie-2) that characterize their phenotype. Angiogenesis is the growth of new blood vessels from preexisting ones and is required for growth and repair. Malignancy is a pathological scenario that requires angiogenesis. The definite cellular origin of adult blood vessel-forming cells necessary for neoangiogenesis has been unknown. Weissman and fellow coworkers in their previous work indicated that the address of these cells might be local, residing in non-circulating tissue. Also, very low numbers of cells with endothelial characteristics and high proliferative potential have been reported in umbilical cord blood or in peripheral blood. The function of circulating endothelial progenitor cells and pharmacotherapy targeted at the endogenous augmentation of these cells for their use in cardiovascular repair has been discussed in detail in a post authored by Aviva Lev-Ari on August 28, 2012.
Research
Scientists at the University of Helsinki, Finland, wanted to find out if there exists a rare vascular endothelial stem cell (VESC) population that is capable of producing very high numbers of endothelial daughter cells, and can lead to neovascular growth in adults. They were not only able to define the characteristic cells responsible for giving rise of blood vessels in adults, but took a leap forward by generating blood vessels from a single cells from the VESC population. (Figure: VESCs discovered that reside at the blood vessel wall endothelium. These are a small population of CD117+ ECs capable of self-renewal. Image Courtesy: Fang et al, 2012).
The VESCs, as explained by the Fang and coworkers, reside in the blood vessel wall endothelium and constitute a small subpopulation within CD117+ (c-kit+) endothelial cells (ECs). These cells are capable of undergoing clonal expansion unlike the surrounding ECs that bear limited proliferating potential. VESC discovered in this study were found to a have a certain characteristic phenotype defined by the presence of a few surface proteins. The authors utilized the technique of FACS (Fluorescence Activated Cell Sorting) to isolate the cells capable of undergoing clonal expansion. The sorting was performed against endothelial-specific protein markers CD31 and CD15, and against CD117 and Sca-1 molecules that are expressed by many adult stem cell types including hematopoietic stem cells (HSCs) and prostate and mammary gland stem cells. The experimental results defined the surface characteristics or the phenotype of the isolated cells to be lin2CD31+CD105+Sca1+CD117+A. A single VESC cell isolated from the endothelial population was able to generate functional blood vessels that connected to host circulation after transplantation in mouse. In cell culture, these cells were shown to generate tens of millions of daughter endothelial cells. Also, within cell culture, the isolated VESCs showed long-term self-renewal properties, bearing similarity to adult stem cells. The self-renewal capacity of VESCs was evident even in vivo, when the ‘isolated’ ECs containing VESCs retained the capacity to generate functional blood vessels during serial transplantations. The transplanted ECs were monitored with the help of Green Fluorescent protein (GFP). Fluorescent blood vessels were observed in secondary, tertiary, and quaternary transplants providing direct evidence that the GFP-tagged ECs contained VESCs with self-renewal capacity.
Furthermore, the cell culture and animal experiment results were supported by the observation that abundant CD117+ ECs were discovered in human malignant melanomas and invasive breast cancer samples.
Research relevance
The discovery of VESCs is seminal and could be of tremendous therapeutic potential. It could be useful in the following ways leading way for related research endeavors including-
- Cell-based therapies: VESCs could be used in cell-based therapies for cardiovascular repair to restore tissue vascularization i.e., the daughter cells arising from VESCs at the target site could assist in repair by generation of neoangiogenic ECs required for the formation of blood vessels.
- Therapeutic target: VESCs could serve as a possible cellular and molecular target to restrain angiogenesis by inhibiting endothelial-cell proliferation thereby blocking cancer progression.
Sources:
Fang S et al, Generation of Functional Blood Vessels from a Single c- kit + Adult Vascular Endothelial Stem Cell. PLoS Biol. 2012;10(10):e1001407. http://www.ncbi.nlm.nih.gov/pubmed/23091420
Related reading:
Cardiovascular and endothelial cells
Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation Curator, Author,Writer, Reporter: Larry Bernstein, MD, FCAP
Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs Author and Curator: Aviva Lev-Ari, PhD, RN
Vascular Medicine and Biology: Macrovascular Disease – Therapeutic Potential of cEPCs Curator and Author: Aviva Lev-Ari, PhD, RN
Repair damaged blood vessels in heart disease, stroke, diabetes and trauma: Cellular Reprogramming amniotic fluid-derived cells into Endothelial Cells Reporter: Aviva Lev-Ari, PhD, RN
Stem cells in therapy
A possible light by Stem cell therapy in painful dark of Osteoarthritis” – Kartogenin, a small molecule, differentiates stem cells to chondrocyte, healthy cartilage cells Author and Reporter: Anamika Sarkar, Ph.D and Ritu Saxena, Ph.D.
Human embryonic pluripotent stem cells and healing post-myocardial infarction Author: Larry H. Bernstein, MD
Stem cells create new heart cells in baby mice, but not in adults, study shows Reporter: Aviva Lev-Ari, PhD, RN
Stem cells for the rescue of mitochondrial dysfunction in Parkinson’s disease Reporter: Ritu Saxena, Ph.D.
Stem Cell Research — The Frontier is at the Technion in Israel Reporter: Aviva Lev-Ari, PhD, RN
Research articles by MA Gaballa, PhD
Harris DT, Badowski M, Nafees A, Gaballa MA. The potential of Cord Blood Stem Cells for Use in Regenerative Medicine. Expert Opinion in Biological Therapy 2007. Sept 7(9): 1131-22.
Furfaro E, Gaballa MA. Do adult stem cells ameliorate the damaged myocardium?. Human cord blood as a potential source of stem cells. Current Vascular Pharmacology 2007, 5; 27-44.
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Dr. Ritu,
Thank you for all the additions to the post.
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
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This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.
A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.