Connective tissue fibroblast properties are position-dependent during mouse digit tip regeneration

Area of Science:

• Regenerative Biology
• Mammalian Limb Regeneration
• Connective Tissue Cell Biology

Background:

• Salamanders regenerate limbs using positional cues, unlike mammals with limited regenerative capacity.
• Mammalian digit regeneration is level-dependent, with distal (P3) digits regenerating but proximal (P2) digits failing.
• The role of connective tissue cells in mammalian digit regeneration remains unclear.

Purpose of the Study:

• To investigate the role of connective tissue cells in mammalian digit regeneration.
• To compare the characteristics of connective tissue cells from regeneration-competent (P3) and incompetent (P2) digit levels.

Main Methods:

• Isolation and in vitro culture of connective tissue cells from P2 and P3 mouse digit levels.
• Assessment of cell proliferation, epithelial progenitor interactions, and 3D culture behavior.
• In vivo engraftment studies to evaluate cell survival and proliferation in a regenerative environment.

Main Results:

• P2 and P3 connective tissue cells, despite proximity, display distinct in vitro and in vivo profiles.
• Both cell types can organize and differentiate epithelial progenitors, but with differing outcomes.
• P3 cells lack the contractile response observed in P2 cells and other fibroblasts.
• In vivo, P2 and P3 cells show distinct survival and proliferative indices during regeneration.

Conclusions:

• Connective tissue cells possess distinct positional characteristics linked to their regenerative capabilities.
• These findings highlight the importance of positional cues in mammalian digit regeneration.
• The study provides the first evidence of differential regenerative potential in mammalian digit connective tissue cells based on their location.