Damaged or diseased organs may someday be healed with an injection of blood vessel cells, eliminating the need for donated organs and transplants, according to scientists at Weill Cornell Medical College.
In studies appearing in recent issues of Stem Cell Journal and Developmental Cell, the researchers show that endothelial cells -- the cells that make up the structure of blood vessels -- are powerful biological machines that drive regeneration in organ tissues by releasing beneficial, organ-specific molecules.
They discovered this by decoding the entirety of active genes in endothelial cells, revealing hundreds of known genes that had never been associated with these cells. The researchers also found that organs dictate the structure and function of their own blood vessels, including the repair molecules they secrete.
Together, the studies show that endothelial cells and the organs they are transplanted into work together to repair damage and restore function, says the study's lead investigator, Shahin Rafii, M.D., a professor of genetic medicine and co-director of the medical college's Ansary Stem Cell Institute and Tri-SCI Stem Center. When an organ is injured, its blood vessels may not be able to repair the damage on their own because they may themselves be harmed or inflamed, says Dr. Rafii, who is also an investigator at the Howard Hughes Medical Institute.
"Our work suggests that that an infusion of engineered endothelial cells could engraft into injured tissue and acquire the capacity to repair the organ," he says. "These studies -- along with the first molecular atlas of organ-specific blood vessel cells reported in the Developmental Cell paper-- will open up a whole new chapter in translational vascular medicine and will have major therapeutic application.
"Scientists had thought blood vessels in each organ are the same, that they exist to deliver oxygen and nutrients. But they are very different," and each organ is endowed with blood vessels with unique shape and function and delegated with the difficult task of complying with the metabolic demands of that organ, Dr. Rafii adds.
The scientists developed technology that helped them obtain "a pure population of endothelial cells in a very rapid time frame," says the study's lead author, Dr. Daniel Nolan, a senior scientist in Dr. Rafii's laboratory during this study who became an employee of Angiocrine Bioscience after it was completed. AB is housed at Weill Cornell Medical College and founded on various technologies based on Dr. Rafii's work.
From these cells, they were able to take a snapshot of all the genes that are being expressed in the various populations of endothelial cells known as vascular beds.
They found that endothelial cells possess tissue-specific genes that code for unique growth factors, adhesion molecules, and factors regulating metabolism. "We knew that these gene products were critical to the health of a particular tissue, but before our study it was not appreciated that these factors originate in the endothelial cells," Dr. Nolan says.
"We also found that the healing, or regeneration of tissue, in the liver and in the bone marrow were unexpectedly different -- including the repair molecules, known as angiocrine growth factors, that were expressed by the endothelial cells," says Dr. Olivier Elemento, who performed the complex computational calculations for the studies.
Blood vessels differ among various organs because the endothelial cells have to constantly adapt to the metabolic, biomechanical, inflammatory and immunological needs of that particular organ, says Dr. Michael Ginsberg, a senior postdoctoral associate in Dr. Rafii's laboratory during this study. Ginsberg also became an employee of Angiocrine Bioscience after the study ended. "And we have now found how endothelial cells have learned to behave differently in each organ and adjust to the needs of those organs," he says.
These findings raise the question as to how endothelial cells have the capacity to adapt to the biological demands of each organ. Is it possible to design "immature" endothelial cells that could allow scientists to identify the means by which the microenvironmental cues educate them to become more specialized endothelial cells?"Versatile endothelial cells" for organ therapy
These embryonic-derived endothelial cells "are versatile, so they can be transplanted into different tissues, become educated by the tissue, and acquire the characteristics of the native endothelial cells," says the study's senior author, Dr. Sina Rabbany, an adjunct associate professor of genetic medicine and bioengineering in medicine at Weill Cornell Medical College.
Dr. Rabbany says researchers can propagate these cells in large numbers in the laboratory. "We now know what it takes to keep these cells healthy, stable and viable for transplantation," he says.
In fact, in the Developmental Cell study, the researchers transplanted these generic endothelial cells generated by Dr. Rabbany's team into the liver of a mouse and found that it became indistinguishable from native endothelial cells. This also occurred when cells were grafted into kidneys. "These naive endothelial cells acquire the phenotype -- the molecular profile and signature -- of the native pre-existing endothelial cells due to the unique microenvironment in the organ," Dr. Ginsberg says.
"These transplanted endothelial cells are being educated by the unique biophysical mincroenvironment organ in which they are placed. They morph into endothelial cells that belong in the organ, and that can repair it," he adds. "If you have a heart injury and you need to reform some of your cardiomyocytes, the endothelial cells that are around the heart secrete factors that are specific for helping a heart repair itself," Dr. Rabbany says.
However, to translate these studies to the clinical setting the scientists have to generate endothelial cells that have similar immune constitution –"immunocompatible" with the recipient patient. "Endothelial cells could be derived from human embryonic pluripotent stem cells as well as by somatic cell nuclear transfer (SCNT)," says Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and director of the Stem Cell Derivation Laboratory of Weill Cornell Medical College and a co-author on the studies. "In the SCNT approach, the nucleus of a somatic cell is introduced into the human egg resulting in the generation of embryonic stem cells that would generate endothelial cells that are a genetic match of the patient," says Dr. Daylon James, assistant professor of reproductive biology at Weill Cornell, who was instrumental in designing protocols to generate endothelial cells from human embryonic stem cells.
"Alternatively, to overcome the bioethical issues associated with human embryos or eggs and potential predisposition of the embryonic stem cells to produce cancer cells, one can take cells discarded after a diagnostic prenatal amniocentesis and turn them into endothelial cells capable of repairing and regenerating blood vessels. Freezing and stockpiling such cells will allow transplantation of these cells to a genetically diverse population of patients," adds Dr. Rosenwaks, referring to work published last October in the journal Cell. Ginsberg is an inventor on this technology, which Angiocrine has licensed.
Additional preclinical investigation is required before study of endothelial cell transplantation in humans is possible, but the therapeutic potential of endothelial cell transplantation is endless, Dr. Rafii says. "They could also be used as Trojan horses to block tumor growth, they could be altered to carry toxic chemicals. They could become biological cruise missiles, directed to do many things inside diseased organs," he says. "Our work has just begun."
The Stem Cell Journal and Developmental Cell studies were funded by the Ansary Stem Cell Institute, the Howard Hughes Medical Institute, the Empire State Stem Cell Board, the New York State Department of Health (NYSTEM C024180, C026438, and C026878), the National Institutes of Health (R01s HL097797 and DK095039), the Qatar National Priorities Research Foundation (NPRP08-663-3-140), and the Qatar Foundation BioMedical Research Program (BMRP).
Dr. Rafii, Dr. Nolan, Dr. Ginsberg, and Dr. Rabbany were authors on both studies, as were Dr. Edo Israely, Dr. Bi-Sen Ding, Dr. Daylon James and Dr. Oliver Elemento, all from Weill Cornell Medical College.
Additionally, Brisa Palikuqi, Michael G. Poulos, William Schachterle,Ying Liu, Zev Rosenwaks, Jason M. Butler, Jenny Xiang, Arash Rafii and Koji Shido, all from Weill Cornell Medical College, participated in the Developmental Cell study.
Ginsberg and Nolan received salary support from Angiocrine Biosciences after becoming employees. The Weill Cornell Center for Technology Enterprise and Commercialization has filed a patent application on inventions emanating from the material covered in the Developmental Cell paper and that Ginsberg and Nolan are inventors on.Weill Cornell Medical College
Sarah Smith | EurekAlert!
Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University
Direct conversion of non-neuronal cells into nerve cells
03.07.2018 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
16.07.2018 | Physics and Astronomy
16.07.2018 | Life Sciences
16.07.2018 | Earth Sciences