Showing posts with label regeneration. Show all posts
Showing posts with label regeneration. Show all posts

Tuesday, 20 August 2013

Instructions for planarian regeneration provided by muscle cells

Main Category: Biology / Biochemistry
Article Date: 20 Aug 2013 - 1:00 PDT Current ratings for:
Instructions for planarian regeneration provided by muscle cells
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By studying the planarian flatworm, a master of regenerating missing tissue and repairing wounds, Whitehead Institute Member Peter Reddien and his lab have identified an unexpected source of position instruction: the muscle cells in the planarian body wall.

"I was completely surprised. We had no idea it would be muscle," says Reddien, who is also an associate professor of biology at MIT. "Finding such a cellular system for positional control in an adult regenerative animal was unanticipated and is very informative for understanding regeneration."

For decades, researchers studying regeneration have focused on stem cells, largely because of their ability to spawn almost any type of replacement cell. In fact, the Reddien lab recently determined that cells known as cNeoblasts are the planarian stem cells that are able to regenerate all tissues in these animals.

Long neglected, however, has been the question of cell identity: how do cNeoblasts know where they are and which cells are needed to recreate missing tissues?

The Reddien lab and other labs had already identified various planarian genes involved in imparting positional information during regeneration and adult tissue maintenance, including regulators of Wnt, Bmp, and Fgf signaling pathways. These position control genes (PCGs) are highly conserved and many are found in other animals, including humans. But the cellular location of where those signals originated was unknown.

Reddien hypothesized that a certain type of cell expresses PCGs, possibly a unique type of cell that had not yet been described. To identify these cells, Jessica Witchley and Mirjam Mayer studied PCG expression in planarians and determined that all tested PCGs are indeed expressed in the same cells. They found that collagen, a telltale marker of planarian muscle cells, is also expressed in the same cell population. When part of a planarian was cut off, the muscle cells in the body wall altered which PCGs they expressed in response to the wounding. The lab's results are described in the August 29 issue of Cell Reports.

Until now, the planarian's muscles in the body wall were thought to primarily allow the worms to twist, turn, and respond to touch, in addition to providing some structure to their boneless bodies. Yet, these functions may also explain why muscle cells are so well suited to secrete the proteins coded for by the PCGs.

"Because the muscle cells extend throughout the organism, from head to tail, they are a great way to influence delivery of the PCGs' proteins and get signaling throughout the animal," says Witchley, a co-first author of the Cell Reports paper and a former technician in the Reddien lab. "Because the muscle fibers are long, when you cut the animal, it can immediately respond by contracting to close the wound, turning on wound-induced genes at that site, and eventually changing the pattern of expression to respond to the missing tissue."

The discovery of muscle cells' remarkable role in regeneration opens whole new areas of research.

"For one, we'd like to know how information from muscle cells at the wound site is actually conveyed to the stem cells and how the stem cells receive that information and respond," says Mayer, co-first author and former postdoctoral researcher in the Reddien lab. "And it would be very interesting to see if muscle cells have a position control role in other animals that is similar to what we've found in planarians."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our biology / biochemistry section for the latest news on this subject.

This work is supported by the National Institutes of Health (NIH grant R01GM080639), the Keck Foundation, and the Helen Hay Whitney Foundation.

Written by Nicole Giese Rura

Peter Reddien's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute Investigator and an associate professor of biology at Massachusetts Institute of Technology.

Full Citation:

"Muscle Cells Provide Instructions for Planarian Regeneration"

Cell Reports, 15 August 2013; 10.1016/j.celrep.2013.07.022

Jessica N. Witchley (1,2), Mirjam Mayer (1,2), Daniel E. Wagner (1), Jared H. Owen (1), and Peter W. Reddien (1).

1. Howard Hughes Medical Institute, Whitehead Institute, and Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA

2. These authors contributed equally to this work

Whitehead Institute for Biomedical Research

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Friday, 16 August 2013

Decellularized mouse heart beats again after regeneration with human heart precursor cells in Pitt project

Main Category: Cardiovascular / Cardiology
Also Included In: Biology / Biochemistry
Article Date: 15 Aug 2013 - 2:00 PDT Current ratings for:
Decellularized mouse heart beats again after regeneration with human heart precursor cells in Pitt project
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For the first time, a mouse heart was able to contract and beat again after its own cells were stripped and replaced with human heart precursor cells, said scientists from the University of Pittsburgh School of Medicine. The findings, reported online in Nature Communications, show the promise that regenerating a functional organ by placing human induced pluripotent stem (iPS) cells - which could be personalized for the recipient - in a three-dimensional scaffold could have for transplantation, drug testing models and understanding heart development.

In the United States, one person dies of heart disease every 34 seconds, and more than 5 million people suffer from heart failure, meaning a reduced ability to pump blood, said senior investigator Lei Yang, Ph.D., assistant professor of developmental biology, Pitt School of Medicine. More than half of heart disease patients do not respond to current therapies and there is a scarcity of donor organs for transplant.

"Scientists have been looking to regenerative medicine and tissue engineering approaches to find new solutions for this important problem," Dr. Yang said. "The ability to replace a piece of tissue damaged by a heart attack, or perhaps an entire organ, could be very helpful for these patients."

For the project, the research team first "decellularized," or removed all the cells, from a mouse heart, a process that takes about 10 hours using a variety of agents. Then, they repopulated the remaining heart framework, or scaffold, with multipotential cardiovascular progenitor (MCP) cells. These replacement cells were produced by reverse engineering fibroblast cells from a small skin biopsy to make induced pluripotent stem cells and then treating the iPS cells with special growth factors to further induce differentiation.

"This process makes MCPs, which are precursor cells that can further differentiate into three kinds of cells the heart uses, including cardiomyocytes, endothelial cells and smooth muscle cells," Dr. Yang explained. "Nobody has tried using these MCPs for heart regeneration before. It turns out that the heart's extracellular matrix - the material that is the substrate of heart scaffold - can send signals to guide the MCPs into becoming the specialized cells that are needed for proper heart function."

After a few weeks, the mouse heart had not only been rebuilt with human cells, it also began contracting again, at the rate of 40 to 50 beats per minute, the researchers found. More work must be done to make the heart contract strongly enough to be able to pump blood effectively, and to rebuild the heart's electrical conduction system correctly so that the heart rate speeds up and slows down appropriately.

In the future, it might be possible to take a simple skin biopsy from a patient to derive personalized MCPs that can be used to seed a biologic scaffold and regenerate a replacement organ suitable for transplantation, Dr. Yang noted. The model also could be used as a lab-based method to preclinically test the effect of new drugs on the heart or to study how the fetal heart might develop.

"One of our next goals is to see if it's feasible to make a patch of human heart muscle," he added. "We could use patches to replace a region damaged by a heart attack. That might be easier to achieve because it won't require as many cells as a whole human-sized organ would."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cardiovascular / cardiology section for the latest news on this subject.

The project was funded by the University of Pittsburgh, the American Heart Association, and the National Science Council (Taiwan).

Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells

Nature Communications 4, Article number: 2307 doi:10.1038/ncomms3307

Tung-Ying Lu, Bo Lin, Jong Kim, Mara Sullivan, Kimimasa Tobita, Guy Salama & Lei Yang

University of Pittsburgh

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Monday, 5 August 2013

Study offers promising new direction for organ regeneration and tissue repair

Main Category: Biology / Biochemistry
Also Included In: Rehabilitation / Physical Therapy
Article Date: 02 Aug 2013 - 1:00 PDT Current ratings for:
Study offers promising new direction for organ regeneration and tissue repair
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Because most human tissues do not regenerate spontaneously, advances in tissue repair and organ regeneration could benefit many patients with a wide variety of medical conditions.

Now a research team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and Dana-Farber/Boston Children's Cancer and Blood Disorders Center has identified an entirely new approach to enhance normal tissue growth, a finding that could have widespread therapeutic applications.

Their findings were published on-line in the Proceedings of the National Academy of Sciences (PNAS).

Tissue regeneration is a process that is not fully understood, but previous research has demonstrated that endothelial cells lining the insides of small blood vessels play a key role in tissue growth. It is also known that these endothelial cells generate chemical messengers called epoxyeicosatrienoic acids (EETs), which stimulate blood vessel formation in response to tissue injury.

In this new research, first author Dipak Panigrahy, MD, an investigator in BIDMC's Center for Vascular Biology Research, and his colleagues wanted to find out how EETs might participate in organ and tissue regeneration. To answer this question, they created seven different mouse models. The models focused on liver, kidney and lung regeneration; wound healing; corneal vascularization; and retinal vascularization.

"We used genetic and pharmacologic tools to manipulate EET levels in the animals to show that EETs play a critical role in accelerating tissue growth, providing the first in vivo demonstration that pharmacological modulation of EETs can affect organ regeneration," explains Panigrahy, an Instructor in Pathology at Harvard Medical School. Administering synthetic EETs spurred tissue growth in the research models; conversely, lowering EET levels - by either manipulating genes or administering drugs - delayed tissue regeneration.

The team also demonstrated that proteins called soluble epoxide hydrolase (sEH) inhibitors, known to elevate EET levels, promoted liver and lung regeneration. (sEH is the main metabolizing enzyme of EETs.)

"Our results offer a mechanistic rationale for evaluating sEH inhibitors as novel therapeutics for a number of human diseases such as hepatic insufficiency after liver damage and diseases characterized by immature lung development, such as bronchopulmonary dysplasia," says Panigrahy, adding that the use of topical sEH inhibitors on the skin might also be useful for the acceleration of wound healing.

The researchers suspected that EETs were stimulating tissue regeneration by way of blood vessel formation, specifically by producing vascular endothelial growth factor (VEGF) to promote vessel growth. As predicted, when the investigators depleted VEGF in the mice, EETs' effects on organ regeneration disappeared.

"Discovering EETs' role could be of critical importance to help control the repair of liver, lungs and kidneys," says senior author Mark Kieran, MD, PhD, of the Division of Pediatric Oncology at Dana-Farber/Boston Children's Cancer and Blood Disorders Center. "Since diseases of these organs are a major cause of morbidity and mortality in the North American population, the opportunity to modulate the regeneration of healthy tissue could have significant therapeutic implications for many patients." These findings may also apply to conditions or physical defects that lead to the loss of specialized cells in other organ systems, such as the nervous system and the immune system.

The investigators stress that it will be important to determine whether EETs affect other factors, besides VEGF, in influencing tissue repair. Additionally, they add, the beneficial effects of EETs will have to be carefully weighed against their finding that direct administration of EETs can stimulate cancer growth in animal models. Several clinical trials that are currently testing the potential of sEH inhibitors for purposes other than organ regeneration or wound repair could offer valuable insights into the safety of elevating EET levels in patients.

"Although our work suggests synthetic EETs would promote wound healing after surgery, more clinical trials are needed to assess the potential benefits and possible risks of these novel lipids," adds co-corresponding author Darryl Zeldin, MD, Scientific Director for the National Institute of Environmental Health Sciences, part of the National Institutes of Health.

In addition to laying the groundwork for future research, the investigators point out that this study highlights the benefits of experts from varying disciplines and organizations working together, noting that coauthors work in departments ranging from oncology to ophthalmology and from pharmacotherapy to transplantation. They included investigators from Boston Children's Hospital; the Institute for Systems Biology; the University of California, Davis; the National Institute of Environmental Health Science at the National Institutes of Health; the University of North Carolina at Chapel Hill; the Lahey Clinic Medical Center; the University of Texas Southwestern Medical Center; the Fred Hutchinson Cancer Research Center; and Schepens Eye Research Institute/Massachusetts Eye and Ear.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our biology / biochemistry section for the latest news on this subject.

Epoxyeicosanoids promote organ and tissue regeneration, PNAS published online before print July 29, 2013, doi: 10.1073/pnas.1311565110

In addition to Panigrahy, Kieran and Zeldin, coauthors include Bruce D. Hammock (co-corresponding author); Brian T. Kalish, Sui Huang, Diane R. Bielenberg, Hau D. Lee, Jun Yang, Matthew L. Edin, Craig R. Lee, Ofra Benny, Dayna K. Mudge, Catherine E. Butterfield, Akiko Mammoto, Tadanori Mammoto, Bora Inceoglu, Roger L. Jenkins, Mary A. Simpson, Tomoshige Akino, Fred B. Lih, Kenneth B. Tomer, Donald E. Ingber, John R. Falck, Vijaya L. Manthati, Arja Kaipainen, Patricia A. D'Amore, and Mark Puder.

This work was supported by grants from the National Cancer Institute (RO1CA148633-01A4); the Stop and Shop Pediatric Brain Tumor Fund; the C. J. Buckley Pediatric Brain Tumor Fund; the Children's Hospital Boston Surgical Foundation and the Vascular Biology Program; the Robert A. Welch Foundation (GL625910); the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 025034 and Z01 050167); the National Institutes of Health (R01 GM088199; GM31278; R01 ES002710; R01 ES013933, and CA045548; and the NIEHS Superfund Basic Research Program (NIH Grant P42 ES004699). The work was also supported through the Joshua Ryan Rappaport Fellowship and Howard Hughes Medical Institute Research Fellowship.

Beth Israel Deaconess Medical Center

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