p53 and it’s application to human limb regeneration

Michael has explored human limb regeneration for height increase in the past.

Retinoic Acid is mentioned as a key to human limb regeneration and p53 has been implicated as being modified by Retinoic Acid in a number of studies.  If we can find a protein link such as p53 that is important to limb regeneration and supplements to modify expression of that protein than perhaps we can use that information to grow taller.

In one instance, p53 activation due to Endoplasmic Reticulum stress resulted in dedifferentiation of hypertrophic chondrocytes into proliferative chondrocytesThe p53 pathway can be activated by a variety of oxidative and mechanical stresses.  Since activation of p53 is so common it’s unlikely that stimulating p53 is key to stimulating the processes of limb regeneration.  p53 activation is likely a necessary but not sufficient condition.

Regulation of p53 is critical for vertebrate limb regeneration.

“Extensive regeneration of the vertebrate body plan is found in salamander and fish species. In these organisms, regeneration takes place through reprogramming of differentiated cells, proliferation, and subsequent redifferentiation of adult tissues{so humans are likely missing one of these stages likely the reprogramming, can we induce this reprogramming with physical stimulus or supplements?}. Such plasticity is rarely found in adult mammalian tissues, and this has been proposed as the basis of their inability to regenerate complex structures.  Here, we analyzed the role of the tumor-suppressor p53 during salamander limb regeneration. The activity of p53 initially decreases and then returns to baseline. Its down-regulation is required for formation of the blastema, and its up-regulation is necessary for the redifferentiation phase{Since MAPK p38 activates p53, MAPK p38 levels may need to have similar trends as p53 levels during chondrogenic differentiation}. Importantly, we show that a decrease in the level of p53 activity is critical for cell cycle reentry of postmitotic, differentiated cells, whereas an increase is required for muscle differentiation. In addition, we have uncovered a potential mechanism for the regulation of p53 during limb regeneration, based on its competitive inhibition by ΔNp73. The regulation of p53 activity is a pivotal mechanism that controls the plasticity of the differentiated state during regeneration.”

To form a new growth plate you don’t necessarily have to form a blastema, thus reducing p53 levels may not be required.  Just inducing chondrogenic differentiation in MSCs may be enough.

“In salamanders, such as the newt and axolotl, limb regeneration depends on the formation of
a blastema, a mound of progenitor cells of restricted potential that arises after amputation. Following a period of proliferation, blastema cells redifferentiate and restore the structures of the limb.”

“Upon amputation, muscle, cartilage, and connective tissue cells underneath the injury site lose their differentiated characteristics and reenter the cell cycle to give rise to the blastema”

“inhibiting p53 disrupts limb regrowth in salamanders”

“a decrease in the expression levels of Gadd45 and Mdm2 between the early (9 d postamputation, dpa) and late (18 dpa) bud stages, corresponding to the period of blastema formation, followed by a return to the initial levels upon redifferentiation”

“α-pifithrin [is] a p53 inhibitor and nutlin3a [is] a p53 stabilizer, which disrupts the p53–Mdm2 interaction”

“Stabilization of the p53 level at the time of blastema formation, when it normally decreases, led to an impairment of the regeneration process”

“[There exists] upper and lower thresholds of p53 activity, above or below which blastema formation is impaired.”

“the overexpression of the p53 dominant-negative construct DDp53, from the mid-bud stage onwards, resulted in delayed and defective regeneration”<-But not completely absent which means that if a way to inhibit p53 is not found it does not mean completely inhibited regeneration.

“[UV light results] in p53 stabilization and up-regulation of Gadd45 [in both humans and salamanders]”

P53 levels are self reduced because p53 produces MDM2 which degrades p53.  Unless there is oxidative or mechanical stress, p53 levels tend to degrade.  Perhaps this is why spontaneous chondrogenic differentiation can occur in microgravity where there are no oxidative and mechanical stresses?

One thought on “p53 and it’s application to human limb regeneration

  1. josh

    hey can you look into dentin, tyler posted some things about it, at questforheight and i thought it was really interesting.

    Reply

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