PhD Scientific Days 2025

Molecular Medicine III.

Modulation of Chondroitin Sulfate Proteoglycan Expression to Enhance Enteric Neural Stem Cell Transplantation Efficiency in a Hirschsprung Disease Model

Name of the presenter

Szőcs Emőke

Institute/workplace of the presenter

Department of Anatomy, Histology and Embryology

Authors

Emőke Szőcs¹, Réka Borbála Tóth¹, Ádám Soós¹, Nándor Nagy¹

1: Department of Anatomy, Histology and Embryology, Semmelweis University

Text of the abstract

Introduction: The enteric nervous system (ENS) is essential for gastrointestinal function, and developmental disorders of the ENS lead to severe congenital neurointestinal diseases. ENS development involves the migration, proliferation, and differentiation of enteric neural crest-derived cells (ENCCs). These processes are controlled by the mesenchymal environment and regulated by signaling molecules like endothelin-3, BMP4, and WNT11, along with components of the extracellular matrix (ECM). ECM molecules, such as fibronectin and laminin, support cell migration, while others, like chondroitin sulfate proteoglycans (CSPGs), act as inhibitory barriers. Hirschsprung disease is an enteric neurocristopathy marked by impaired gut motility due to missing enteric ganglia in parts of the colorectum. Although enteric neural stem cell (ENSC) transplantation has been explored as a potential therapy, poor cell survival, integration, and migration lead to limited restoration of gut function in Hirschsprung disease models.
Aims: This study aims to identify and characterize microenvironmental factors that improve ENSC transplantation efficiency, focusing on understanding and modifying the effects of non-permissive ECM molecules in Hirschsprung disease models.
Methods and Results: Immunohistochemical analysis of embryonic day (E)5-E10 chicken hindgut shows dynamic expression of CSPGs in the gut mesenchyme. In vitro cell migration experiments reveal that CSPGs inhibit ENCC migration, an effect reversed by chondroitinase ABC (chABC) treatment. Additionally, chABC alters ENCC migration patterns and disrupts concentrically migrating ENCCs within the gut wall. Transplantation of enteric neurospheres into the hindgut shows limited migration from the transplantation site. Recombinants cultured with 1U/ml chABC exhibit enhanced migration upon transplantation.
Conclusion: We hypothesize that increased CSPG expression inhibits ENSC migration, integration, and survival in the intestinal wall. Modulating these proteins in the postnatal environment can enhance the success of cell replacement therapies for neurointestinal diseases.

Funding: OTKA-K-138664, Semmelweis 250+ Scholarship for PhD Excellence, 2024-2.1.1-EKÖP-2024-00004 University Research Scholarship Programme of The Ministry for Culture and Innovation from the source of The National Research, Development and Innovation Fund