Tissue regeneration

Researchers identify a novel approach to enhance tissue growth

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 this week 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.

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 is a patient care, teaching and research affiliate of Harvard Medical School, and currently ranks third in National Institutes of Health funding among independent hospitals nationwide.

BIDMC has a network of community partners that includes Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, Signature Health Care, Commonwealth Hematology-Oncology, Beth Israel Deaconess HealthCare, Community Care Alliance, and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Senior Life and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit bidmc.org.

7 Replies

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  • Is all very complex business ... A was reading about scar tissue and how thay are trying to sofen up the stuff

    A was looking at some scar tissue under microscope it looks white in naked eye but was black and a lose mess under a microscope

    A was thinking is this why my lungs are so ##### if thats what scar tissue is like

    The stuff needs to pull its self together becouse its a mess and needs to get a grip

    Great post glad some are looking into it :)

    O ye found out its black and such a mess becouse when its healing your stretching it and the blood vesals thus it as to dobble up

    Is complex but like a say great post :)

  • hi dazisnotsogood ive just read that the chmp as approved a new once daily inhaler for hand held inhalers or a neb its called ultibro r breezehaler for lung function and less risk of copd ex cant spell it I mean if we are getting ill have u heard of it,its completed trial 111.so it should be on its way,al be chekin with gps nurse nx week as she never tells me ,I have to tell her.then she says oh I no.take care

  • Hi cheers caroll have seen some stuff about 111 trials but have looked at that much stuff but am sure was inpressed ... But have Lot going on so having to research my case

    Cheers all the best :)

  • hi daz always good if new things are coming out,this 1 as pasted the trials and as been approved for hand halers and nebs ,take care lad

  • hi daz ive just read martins blog I also have googled all that so there is some hope somewere,also ,want to hurry up and stop dancing round ,there are to many ppl ill with lung disease now ,we are all human beings ,hear in Oldham its now sky high with copd ,id never heard of the sod till I was told I had it no thanks to ex gp the bougar,did any 1 read the daily mail on tues I think ,man since he was 39 got told by yes his gp he had asthma,now 62 went to hoz saw a consultant who told him u never had that u have had copd since u was 39,the man was livid ,said gps are a shambles now hes on rite meds is able to walk out of his house 1st time in ages ,if gps over the years had said to us wen we went for abs for chest infections /do u smoke there wud not be so many ill now,but no for years fobbing us of with /oh yes infection hears abs bye bye,the boot should fall on them ,not fit alf to practise

  • Must agree ills of NHS are down to GPs i think ... My GP said my illness was stress nearly killed me with inaction

    Quicker thay find cure the better in in my opinan ... Till then we have look out for each other as a would say most GPs don't care Well unless the under investagation

    Cheers all the best :)

  • well put daz all correct.my ex gp said same ur ok no action needed ,clown,gets me why he still there,never heard bsk of pals there the same usless,ex gp give a friend of mine pills give her 2 heart attacks,cant walk now as a scooter an copd,instead of an xray got pills,another man got pills wat nearly killed him,amazed hes still a gp.think all pi.. in same ,take care an your rite needs to find cures now been to long with everything an nothing seems to happen just I think quik fixes for now ,a joke,take care

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