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H2020Individual fellowship2021–2023

ProxDistReg · Implications of tissue stiffness in growth control during limb regeneration in salamanders (Ambystoma mexicanum)

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2021-05-01 → 2023-04-30
EU contribution
€174,806
Participants
1
Scheme
MSCA-IF

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Results in brief

Implications of tissue stiffness in growth control during limb regeneration in salamanders (Ambystoma mexicanum)

Salamanders are able to regenerate full limbs following amputation and the regenerating limb grows until it catches up with the development of the intact contralateral limb. This is a remarkable example of growth control since the regenerated limb must grow to a size that is larger than it was at the time of amputation in order to accommodate to the animal’s growing body. Even more strikingly, when a salamander is given a complete amputation on one limb and a digit amputation on the other, regeneration of both structures is completed in approximately the same period. Thus, distally amputated limbs grow slower than proximally amputated ones, resulting in an overall length of regeneration that is independent of the tissue volume to be reformed. Although this phenomenon was first observed centuries ago, the underlying mechanisms are still unknown. Furthermore, whether such differences in growth are already encoded in undamaged tissues, or if the differences only arise during regeneration, is undetermined as well. Differential adhesion strength and extracellular matrix (ECM) were reported along the proximodistal (PD) axis during axolotl limb regeneration. Therefore, considering that cell–cell interactions and cell-ECM interactions play key roles in force transmission to and between cells, controlling signalling pathways that regulate stem cell self-renewal and differentiation, we hypothesize that tissue mechanical properties are regulated in gradient along the PD axis and are thus majorly responsible for the differential growth rates observed during regeneration between proximally and distally-amputated limbs. Therefore, the central aim of this project is understanding how biomechanical properties of tissues affect regeneration, which may have important implications for the design of biomaterials to be used in regenerative medicine.

Data: CORDIS, © European Union

Project objective

In several regenerating organisms it has been observed that distally amputated structures grow slower than proximally amputated ones, resulting in an overall time of regeneration that is independent of the tissue to be reformed. This observation suggests that cell proliferation or cell size could be adjusted with the plane of amputation along the proximo-distal (PD) axis, leading to an interesting scaling behaviour. It has been proposed that positional identity in the limb may be encoded as a proximal-to-distal gradient of cell surface molecules, that would in turn alter intercellular adhesions. Thus, it is possible that such differential adhesions are associated to the control of cell growth during regeneration. The central aim of this proposal is to address this question by combining cell biology, mathematical and physical tools, with the ultimate goal of understanding how the biomechanical properties of tissues affect regeneration, which may have important implications for the design of biomaterials aimed at being used for regenerative medicine.We will tackle this question in the highly regenerative salamander species Axolotl mexicanum, in which limb regeneration is initiated regardless of the amputation plane, and the regenerating limb grows until its size matches the contralateral undamaged one. We will evaluate growth rate and cell cycle of regenerating limbs amputated at different levels, and mathematically describe cell proliferation patterns. We will characterize several cell surface and extracellular matrix molecules along the PD axis, and measure tissue mechanics in vivo. Furthermore, we will for the first time, evaluate the Hippo pathway in salamanders, an important modulator of cell growth in response to several physical inputs, as the causal link between increased tissue stiffness and decreased proliferation.

Original text from CORDIS.

Participants

  • TECHNISCHE UNIVERSITAET DRESDEN · DresdenCoordinatorGermany

Links

Data: CORDIS, © European Union