Bio of Aging Paper 4: Rejuvenation of Aged progenitor cells

Hallmark of aging

decline in regenerating tissues

may be due to changes in the stem cells

Notch Signaling

prevents tumor formation

Satellite Cell

Skeletal stem muscle cell

What causes impaired muscle cell regeneration

Loss of Notch signaling:

1. Leads to tumorigenesis'

2. Leads to a decline of satellite cells

What inhibits the regenerative capacity of aged liver

1. Low hepatic progenitor cells

2. Formation of a complex with cEBP-alpha

3. Formation of Brm, a chromatin remodelling factor

What models did they use in this study

Progenitor cells from liver and muscle

Used youth serum on the old mice (heterchronic models), to see if the factors in the young mice would restore rejuvenation in old mice

Results of Exposure to Youth Serum in Muscle

restored Notch signaling

1. Increase the expression of Notch ligand (Delta)

2. increased Notch activation

3. Increased cell proliferation in vitro

Results of Exposure to Youth Serum in Muscle

restored cEBP-alpha complex to levels seen in the young mice

Loss of Notch Signaling

decreased satellite cell activity

impaired regeneration of aged muscle

cannot repair muscle damage

Young Serum in Old Mice & Vice Versa

Aged muscle regenerates with exposed to the muscle of the young host

Young muscle from young mice have impaired regenerative abilities with exposed to aged mice

Hypothesis

Old tissues are able to regenerate as well as young tissues, but their pathways are inhibited

Must be rejuvenated from an old state back to a young state

Heterochronic

Pairings with old and young mice

Isochronic

pairings with old & old, young with young

Parabiosis

Pairings of mice (2 mice into 1) where they will eventually fuse and share the same systemic factors

The mouse models shared a circulatory system to be exposed to the serums

How did they tell which markers were from the young serum

Tag and floures with GFP

How did they detect cell proliferation

BrdU Staining: used to detect cell division history

Injured the hindleg muscles of the mice and then gave BrdU injections

Satellite cells activate

Lead to proliferative myoblasts

Form Myotubes: expressed eMHC, a marker for regenerating myotubes

eMHC

expressed in Myotubes

marker for regeneration myotubes

How to measure robust regeneration

myotubes both appeared centrally nucleated and expressed eMHC

Parabiosis with young mice results in

enhanced regeneration of muscle in old mice

myotubes also looked the same with the young mice

Heterochronic Parabiosis

enhanced proliferation from the old resident cells

restored signaling (Notch) needed for muscle regeration

cEBP-alpha inhibits E2F expression

inhibits proliferation and regenerative abilities