Rejuvenation of aged progenitor cells

Our ageing generally characterized as a progressive decline of tissue and organ function, accompanied by increased oxidative damage, mitochondrial dysfunction, endocrine imbalance and genome instability. Tissue regenerative capacity also declines with age, and in tissues such as muscle, blood, liver and brain.
Now,how will it be,if we can control our age?If we can stay young for ever,how will it be?

It’s too amazing,right??

But it sounds impossible,isn’t it?

Now,if you think so,you are wrong,because our scientists have found a new way of “Rejuvenation of aged progenitor cells”. Signalling through the Notch pathway is essential for the activation, proliferation and myogenic lineage progression of satellite cells necessary for muscle repair, and that the decline in the regenerative potential of muscle with age is due to the failure of this pathway to be activated. Aged muscle successfully regenerates when grafted into muscle in a young host, but young muscle displays impaired regeneration when grafted into an aged host. Old tissues might be made to regenerate as well as young tissues if, by means of systemic influences, the molecular pathways could be ‘rejuvenated’ from an old state to a young state.To test this hypothesis scientists have established parabiotic pairings between young and old mice (heterochronic parabioses), with parabiotic parings between two young mice or two old mice (isochronic parabioses) as controls.

Scientists have examined the efficacy of muscle regeneration in young (2–3 months) and aged (19–26 months) mice in heterochronic and isochronic pairings. Young partners were either transgenic for green fluorescent protein (GFP), allowing confirmation of blood chimaerism. The use of GFP-transgenic mice as one member of a pair also allowed us to distinguish the cells from each animal participating in tissue regeneration. After 5?weeks of parabiosis the hindlimb muscles of each mouse were injured and the mice were given 5-bromodeoxyuridine (BrdU) injections. After muscle injury, satellite cells activate and give rise to proliferative myoblasts, which ultimately fuse to form nascent myofibres, that maintain centrally located nuclei and express embryonic myosin heavy chain (eMHC), a specific marker of regenerating myotubes in adult animals. Five days after injury, muscles in young mice in both isochronic and heterochronic parabioses had regenerated robustly, as demonstrated by the appearance of centrally nucleated, eMHC-expressing myotubes formed from proliferating progenitor cells. In contrast, injured muscle from old isochronic parabionts regenerated poorly, typical of aged animals, with a failure of myotube formation, prominent fibrosis at the site of injury, and evidence of proliferating cells predominantly in the interstitial spaces. Parabiosis with young mice significantly enhanced the regeneration of muscle in old partners. The appearance of nascent myotubes in these old mice was similar to that seen in young mice.

FIG-1

The loss of muscle regeneration with age is due at least in part to an age-related impairment in the upregulation of the Notch ligand Delta after muscle injury.It’s tested whether heterochronic parabiosis restored Delta upregulation in aged satellite cells and thus enhanced their activation and proliferation. Using myofibre explantation to assess satellite cell activation they analysed satellite cells for the expression of Delta.
To determine whether the rejuvenating effects of heterochronic parabiosis could be replicated in an in vitro system, satellite cells, cultured either alone or in association with myofibre explants, were prepared from young and old mice and were cultured in the presence of young or old mouse serum, thus recapitulating the humoral aspects of heterochronic parabioses. Compared with young satellite cells cultured in either young or old serum, there was much less upregulation of Delta in old satellite cells cultured with old mouse serum; however, young mouse serum restored the upregulation of Delta and the activation of Notch in aged satellite cells. There was an inhibitory effect of the old mouse serum on young satellite cells in terms of the upregulation of Delta. Serum from young mice also significantly enhanced the proliferation of myofibre-associated satellite cells in the old cultures compared with serum from old mice . There was reduced proliferation of both young and old satellite cells cultured in young mouse serum when Notch signalling was inhibited. Therefore, enhanced activation and proliferation of aged myogenic progenitor cells by serum from young mice is Notch dependent.

Encouraged by these findings,scientists then examined liver from aged mice subjected to heterochronic parabiosis to test for evidence of a more general capability to rejuvenate aged, resident progenitor cells.They studied proliferating hepatocytes involved in normal tissue turnover, because there is a well documented decline in hepatocyte proliferation with age. Heterochronic and isochronic parabionts were examined for hepatocyte proliferation by two independent criteria: the incorporation of BrdU or expression of the proliferation marker Ki67 in albumin-positive cells. In young isochronic parabionts, the levels of basal hepatocyte proliferation were two to threefold greater than in non-parabiosed controls. Also, clusters of BrdU-positive proliferating cells that were not hepatocytes were observed in aged livers. Proliferation of albumin-positive cells in old isochronic parabionts was less than that observed in young isochronic parabionts.There is an age-related decline in the basal rate of hepatocyte proliferation in non-parabiosed animals. However, parabiosis to a young partner significantly increased hepatocyte proliferation in aged mice.

FIG-2

The age-related decline in hepatocyte proliferation is due to the formation of an age-specific complex of cell cycle regulators associated with cEBP-a that inhibits E2F-driven gene expression. One of the proteins detected in this complex in old, but not young, liver is the chromatin remodelling factor Brm. Levels of the cEBP-a–Brm complex increase in the livers of old rodents, leading to a decline of hepatocyte proliferation. The complex was present at elevated levels in young heterochronic parabionts compared with young controls, also consistent with the modest inhibition of hepatocyte proliferation in young heterochronic parabionts. These data show that the young systemic environment restores a younger profile of molecular signalling to the aged progenitor cells in the liver and also enhances their proliferation.

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The whole experiments suggest that there are systemic factors that can modulate the molecular signalling pathways critical to the activation of tissue-specific progenitor cells, and that the systemic environment of a young animal is one that promotes successful regeneration, whereas that of an older animal either fails to promote or actively inhibits successful tissue regeneration. It will be of great interest to identify the factors that have such a critical influence on tissue-specific progenitor cells. the decline of tissue regenerative potential with age can be reversed through the modulation of systemic factors, suggesting that tissue-specific stem and progenitor cells retain much of their intrinsic proliferative potential even when old.

Now, Happy??!!

Written By,

Shubhankar Kundu

IISER Bhopal


Image Sources: Google.

Further Reading and References:

  • https://static1.squarespace.com/static/5a2069c3ccc5c5325fd05b02/t/5a47495d53450a63fe351654/1514621278260/2005_conboy.pdf
  • https://www.hindawi.com/journals/sci/2018/9308301/
  • https://www.nature.com/articles/nature03260

Author: Shubhankar Kundu

A fifth-year BS-MS student and a DST-INSPIRE fellow at IISER Bhopal, pursuing a major in Chemistry. Loves writing poems and painting during leisure times. Has a knack for music and loves playing the violin. Also, loves reciting Bengali poems and football. A die-hard fan of Netaji Subhas Chandra Bose, the legendary Indian freedom fighter. Exploring unknown places and photography, are some other noteworthy hobbies. Associated with the core team of TQR since 2018.

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