Interplay between Follistatin, Activin A, and BMP4 Signaling Regulates Postnatal Thymic Epithelial Progenitor Cell Differentiation during Aging.

Press/Media: Article/Feature

Description

Cell Rep. 2019 Jun 25;27(13):3887-3901.e4. doi: 10.1016/j.celrep.2019.05.045.

A key feature of immune functional impairment with age is the progressive involution of thymic tissue responsible for naive T cell production. In this study, we identify two major phases of thymic epithelial cell (TEC) loss during aging: a block in mature TEC differentiation from the pool of immature precursors, occurring at the onset of puberty, followed by impaired bipotent TEC progenitor differentiation and depletion of Sca-1lo cTEC and mTEC lineage-specific precursors. We reveal that an increase in follistatin production by aging TECs contributes to their own demise. TEC loss occurs primarily through the antagonism of activin A signaling, which we show is required for TEC maturation and acts in dissonance to BMP4, which promotes the maintenance of TEC progenitors. These results support a model in which an imbalance of activin A and BMP4 signaling underpins the degeneration of postnatal TEC maintenance during aging, and its reversal enables the transient replenishment of mature TECs.

Period25 Jun 2019 → 3 Jul 2019

Media coverage

4

Media coverage

  • TitleDiscovery my help kick-start ageing immune system.
    Degree of recognitionInternational
    Media name/outletscimex
    Media typeWeb
    Duration/Length/Size400 words
    CountryAustralia
    Date29/06/19
    DescriptionThe thymus is the powerhouse producing the immune system’s T cells, which combat infection in our body. Yet this vital organ is one of the first to diminish in function as we age, resulting in a gradual loss of T cell production and eventually increased susceptibility to infections and cancer in the elderly.

    Monash Biomedicine Discovery Institute (BDI) researchers have for the first time identified factors affecting the cells in the thymus that set in train this loss and the mechanisms behind this.

    Moreover, their study, published in Cell Reports today, paves the way to develop targeted strategies for the recovery of T cells to help combat infections and cancers.

    Associate Professor Ann Chidgey, senior author, said it had been known for some time that the thymus – a small organ located below the collarbone – degenerated from puberty onwards. However, the mechanisms underlying this were unclear.

    “Our thymus is most productive soon after birth and produces a full repertoire of T cells, but then slowly begins to lose function. As we live longer, the diversity of our T cells diminishes and we become more susceptible to infections. It also becomes more difficult to recover our T cell immunity after damage from cancer treatments such as chemotherapy which destroy a lot of our immune cells,” she said.

    The paper showed what was behind this degeneration; factors affecting the epithelial stem cells in the thymus.

    “This study identifies BMP4 and Activin, as growth and differentiation factors important for the self-renewal and differentiation of thymic epithelial stem cells, and how a change in their production during ageing causes a loss of mature epithelial cells. This leads to a reduced capacity to support the production of T cells,” Associate Professor Chidgey said.

    “This is the first time anyone has identified the basis for mature thymic epithelial cell loss and the molecules that are involved in the dysfunction of the thymic epithelial stem cells in ageing. By doing this we can now focus on how to reverse that and ‘switch on’ the thymus again, even just transiently, to replenish our T cell diversity,” she said.

    “We believe these changes can be reversed and are beginning new investigations to see if we can develop a treatment focussed on thymic epithelial cell regeneration.”

    Drs Ailin Lepletier and Michael Hun were joint first authors on the paper.

    This research was supported by a National Health and Medical Research (NHMRC) grant.
    Producer/AuthorScimex.org/Aest Nzst
    URLhttps://www.scimex.org/newsfeed/discovery-may-help-kick-start-ageing-immune-system
    PersonsAnn Chidgey
  • TitleDiscovery may help kick-start ageing immune system
    Media name/outletMedical Xpress
    CountryAustralia
    Date25/06/19
    DescriptionThe thymus is the powerhouse producing the immune system’s T cells, which combat infection in our body. Yet this vital organ is one of the first to diminish in function as we age, resulting in a gradual loss of T cell production and eventually increased susceptibility to infections and cancer in the elderly.

    Monash Biomedicine Discovery Institute (BDI) researchers have for the first time identified factors affecting the cells in the thymus that set in train this loss and the mechanisms behind this.

    Moreover, their study, published in Cell Reports today, paves the way to develop targeted strategies for the recovery of T cells to help combat infections and cancers.

    Associate Professor Ann Chidgey, senior author, said it had been known for some time that the thymus – a small organ located below the collarbone – degenerated from puberty onwards. However, the mechanisms underlying this were unclear.

    “Our thymus is most productive soon after birth and produces a full repertoire of T cells, but then slowly begins to lose function. As we live longer, the diversity of our T cells diminishes and we become more susceptible to infections. It also becomes more difficult to recover our T cell immunity after damage from cancer treatments such as chemotherapy which destroy a lot of our immune cells,” she said.

    The paper showed what was behind this degeneration; factors affecting the epithelial stem cells in the thymus.

    “This study identifies BMP4 and Activin, as growth and differentiation factors important for the self-renewal and differentiation of thymic epithelial stem cells, and how a change in their production during ageing causes a loss of mature epithelial cells. This leads to a reduced capacity to support the production of T cells,” Associate Professor Chidgey said.

    “This is the first time anyone has identified the basis for mature thymic epithelial cell loss and the molecules that are involved in the dysfunction of the thymic epithelial stem cells in ageing. By doing this we can now focus on how to reverse that and ‘switch on’ the thymus again, even just transiently, to replenish our T cell diversity,” she said.

    “We believe these changes can be reversed and are beginning new investigations to see if we can develop a treatment focussed on thymic epithelial cell regeneration.”
    URLhttps://medicalxpress.com/news/2019-06-discovery-kick-start-ageing-immune.html
    PersonsAnn Chidgey
  • TitleDiscovery may help kick-start ageing immune system
    Degree of recognitionInternational
    Media name/outletBrightSurf.com
    Media typeWeb
    Duration/Length/Size426 words
    CountryAustralia
    Date25/06/19
    DescriptionThe thymus is the powerhouse producing the immune system's T cells, which combat infection in our body. Yet this vital organ is one of the first to diminish in function as we age, resulting in a gradual loss of T cell production and eventually increased susceptibility to infections and cancer in the elderly.

    Monash Biomedicine Discovery Institute (BDI) researchers have for the first time identified factors affecting the cells in the thymus that set in motion this loss and the mechanisms behind this.

    Their study, published in Cell Reports today, paves the way to develop targeted strategies for the recovery of T cells to help combat infections and cancers.

    Associate Professor Ann Chidgey, senior author, said it had been known for some time that the thymus - a small organ located below the collarbone - degenerated from puberty onwards. However, the mechanisms underlying this were unclear.

    "Our thymus is most productive soon after birth and produces a full repertoire of T cells, but then slowly begins to lose function. As we live longer, the diversity of our T cells diminishes and we become more susceptible to infections," she said.

    "It also becomes more difficult to recover our T cell immunity after damage from cancer treatments such as chemotherapy which destroy a lot of our immune cells."

    The study showed what was behind this degeneration; factors affecting the epithelial stem cells in the thymus.

    "This study identifies BMP4 and Activin, as growth and differentiation factors important for the self-renewal and differentiation of thymic epithelial stem cells, and how a change in their production during ageing causes a loss of mature epithelial cells. This leads to a reduced capacity to support the production of T cells," Associate Professor Chidgey said.

    "This is the first time anyone has identified the basis for mature thymic epithelial cell loss and the molecules that are involved in the dysfunction of the thymic epithelial stem cells in ageing. By doing this we can now focus on how to reverse that and 'switch on' the thymus again, even just transiently, to replenish our T cell diversity," she said.

    "We believe these changes can be reversed and are beginning new investigations to see if we can develop a treatment focussed on thymic epithelial cell regeneration."

    Drs Ailin Lepletier and Michael Hun were joint first authors on the paper.

    This research was supported by a National Health and Medical Research Council (NHMRC) grant.

    Read the full paper in Cell Reports titled Interplay between Follistatin, Activin A, and BMP4 Signaling Regulates Postnatal Thymic Epithelial Progenitor Cell Differentiation during Aging.
    URLhttps://www.brightsurf.com/news/article/062519486364/discovery-may-help-kick-start-ageing-immune-system.html
    PersonsAnn Chidgey
  • TitleDiscovery can help start the aging immune system
    Degree of recognitionInternational
    Media name/outletvaaju.com
    Media typeWeb
    Duration/Length/Size400 words
    CountryAustralia
    Date25/06/19
    DescriptionThe thymus is the powerhouse producing the immune system’s T cells, which combat infection in our body. Yet this vital organ is one of the first to diminish in function as we age, resulting in a gradual loss of T cell production and eventually increased susceptibility to infections and cancer in the elderly.

    Monash Biomedicine Discovery Institute (BDI) researchers have for the first time identified factors affecting the cells in the thymus that set in train this loss and the mechanisms behind this.

    Moreover, their study, published in Cell Reports today, paves the way to develop targeted strategies for the recovery of T cells to help combat infections and cancers.

    Associate Professor Ann Chidgey, senior author, said it had been known for some time that the thymus – a small organ located below the collarbone – degenerated from puberty onwards. However, the mechanisms underlying this were unclear.

    “Our thymus is most productive soon after birth and produces a full repertoire of T cells, but then slowly begins to lose function. As we live longer, the diversity of our T cells diminishes and we become more susceptible to infections. It also becomes more difficult to recover our T cell immunity after damage from cancer treatments such as chemotherapy which destroy a lot of our immune cells,” she said.

    The paper showed what was behind this degeneration; factors affecting the epithelial stem cells in the thymus.

    “This study identifies BMP4 and Activin, as growth and differentiation factors important for the self-renewal and differentiation of thymic epithelial stem cells, and how a change in their production during ageing causes a loss of mature epithelial cells. This leads to a reduced capacity to support the production of T cells,” Associate Professor Chidgey said.

    “This is the first time anyone has identified the basis for mature thymic epithelial cell loss and the molecules that are involved in the dysfunction of the thymic epithelial stem cells in ageing. By doing this we can now focus on how to reverse that and ‘switch on’ the thymus again, even just transiently, to replenish our T cell diversity,” she said.

    “We believe these changes can be reversed and are beginning new investigations to see if we can develop a treatment focussed on thymic epithelial cell regeneration.”

    Drs Ailin Lepletier and Michael Hun were joint first authors on the paper.

    This research was supported by a National Health and Medical Research (NHMRC) grant.
    Producer/AuthorVaaju
    URLhttps://vaaju.com/discovery-can-help-start-the-aging-immune-system/
    PersonsAnn Chidgey

Media contributions

1

Media contributions

  • TitleA step closer to regenerating the aging thymus
    Degree of recognitionInternational
    Media name/outletLife Extension Advocacy Foundation
    Media typeWeb
    Duration/Length/Size810 words
    CountryAustralia
    Date3/07/19
    DescriptionResearchers from the Monash Biomedicine Discovery Institute have made progress in the quest to rejuvenate the aging immune system by identifying the factors responsible for the age-related decline of the thymus.

    The thymus shrinks as we age

    The thymus is one of the most important organs in the body, and it is where thymocytes produced in the bone marrow travel to become new T cells before being trained in the lymph nodes to become the defenders of the adaptive immune system. However, as we get older, the thymus increasingly turns to fat and starts to shrink, causing its ability to produce new T cells to fall dramatically. This process is known as thymic involution and actually begins shortly after puberty, so this is one aspect of aging that begins fairly early in life, although it is many decades later before its decline causes serious health issues.

    The fall in production of new T cells from the thymus results in a decline of the adaptive immune system and is part of the collective decline of the immune system called immunosenescence. The end result of immunosenescence is that your body is no longer able to mount an effective defense against diseases and is inappropriately activated, leading to dysfunction and persistent inflammation. This inflammation contributes to inflammaging, a chronic smoldering background of low-grade inflammation, which other age-related sources contribute to as well.

    The decline of the thymus has been linked to cancer risk, which rises dramatically as we age as part of the immunosenescence model of cancer. Immunosenescence is also strongly correlated with multiple age-related diseases, which is probably no surprise, given that the aged immune system is no longer able to respond effectively or even appropriately to invading pathogens.

    While it has long been known that the thymus shrinks with age, the exact mechanisms behind this involution were not totally clear.

    The downward spiral

    The new study has shed new light on what drives the loss of thymus function in old age and the resulting failure of immune cell production [1]. Published in the journal Cell, the new study lays the foundation for developing therapies that may help the thymus to recover its ability to produce T cells and combat infections and diseases.

    The researchers show that BMP4 and activin are growth and differentiation factors that are key to the self-renewal and differentiation of thymic epithelial stem cells and that a change in their levels due to aging causes the loss of these epithelial cells. This loss then results in the decline of T cell production in the thymus, ultimately leaving us open to infection and disease. This study is a world first and finally identifies the core reason why we experience the loss of thymic epithelial stem cells and the molecules and mechanisms that drive this process.

    The researchers’ next step will be to find ways to reverse this decline and effectively turn the thymus back on again so that T cell production resumes. The researchers believe that age-related changes in the thymus can be reversed, and they are now investigating to see if a therapy to regenerate thymic epithelial stem cells can be created.

    A key feature of immune functional impairment with age is the progressive involution of thymic tissue responsible for naive T cell production. In this study, we identify two major phases of thymic epithelial cell (TEC) loss during aging: a block in mature TEC differentiation from the pool of immature precursors, occurring at the onset of puberty, followed by impaired bipotent TEC progenitor differentiation and depletion of Sca-1lo cTEC and mTEC lineage-specific precursors. We reveal that an increase in follistatin production by aging TECs contributes to their own demise. TEC loss occurs primarily through the antagonism of activin A signaling, which we show is required for TEC maturation and acts in dissonance to BMP4, which promotes the maintenance of TEC progenitors. These results support a model in which an imbalance of activin A and BMP4 signaling underpins the degeneration of postnatal TEC maintenance during aging, and its reversal enables the transient replenishment of mature TECs.

    Conclusion

    Effective targeting of these pathways could lead to restoration of not only thymic T cell production but also T cell diversity. This has the potential to dramatically improve health in older people, who generally have poor or nearly non-functional T cell production as a result of thymic involution. If a therapy can be developed that regenerates the thymus, restoring its function to more youthful levels, it has the potential to improve the health of older people and reduce their risk of contracting a myriad of age-related and non-age-related diseases.

    A number of companies and research teams are now focused on rejuvenation of the thymus, and the evidence to date, including animal studies and even tentative human trials, leads us to believe that regenerating the thymus is a quite possible near-future prospect.
    Producer/AuthorSteve Hill
    URLhttps://www.leafscience.org/a-step-closer-to-regenerating-the-aging-thymus/
    PersonsAnn Chidgey

Keywords

  • immune aging
  • thymus
  • thymus regeneration
  • stem cells
  • thymic epithelial progenitor