The enteric neural crest progressively loses capacity to form enteric nervous system

Area of Science:

• Developmental Biology
• Neuroscience
• Regenerative Medicine

Background:

• The enteric nervous system (ENS) is primarily formed by vagal neural crest (NC) cells colonizing the embryonic gut.
• Enteric neuropathies involve an ENS deficit, leading to suggestions of cell replacement therapy.
• The potential for post-natal ENS cells to retain their embryonic-forming capacity with age is unknown.

Purpose of the Study:

• To investigate the age-dependent changes in the ENS-forming potential of neural crest-derived cells.
• To determine if post-natal ENS cells retain their colonization and differentiation capabilities.
• To inform the optimal strategy for ENS cell-based therapies.

Main Methods:

• Organotypic cultures of aneural chick midgut/hindgut with donor quail ENS cells of varying ages (QE5-QE10).
• In vitro assays and in vivo chorio-allantoic membrane grafts to assess colonization capacity.
• Immunohistochemistry using neural crest, neuron, and glial markers to quantify cell populations.

Main Results:

• ENS cells from young donors (≤ QE6) readily colonized recipient guts, but this capacity rapidly declined post-wavefront transit.
• The loss of colonization ability was intrinsic to the ENS cell population, observed even in isolated HNK1+ cells.
• Older donor cells showed significantly reduced colonization ability compared to younger cells, indicating both quantitative and qualitative declines.

Conclusions:

• The ENS cell population's ability to form the ENS diminishes significantly with age.
• Cell therapies for enteric neuropathies should aim to replicate embryonic ENS cell characteristics, not use post-natal stem/progenitor cells.
• Therapeutic strategies must consider the age-related decline in ENS-forming potential for successful cell replacement.