2023 Fiscal Year Annual Research Report
Assessment of a potential application of endogenous stem cells to treat congenital disorders
| Project/Area Number |
22K20740
|
|---|
| Research Institution | Kobe University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2022-08-31 – 2024-03-31
|
| Keywords | tissue regeneration / enteric nervous system / endogenous stem cell / Hirschsprung disease |
|---|
| Outline of Annual Research Achievements |
Congenital organ deficits often result in impaired organogenesis due to dysfunctional stem cells caused by toxic gene mutations. Current treatments mainly rely on surgical intervention, but their efficacy remains unsatisfactory. One promising approach is harnessing endogenous stem cells for tissue regeneration. With advancements in genome editing, correcting gene mutations to rescue stem cell function in vivo may soon be feasible.
Our study focuses on assessing the regenerative potential of endogenous stem cells for congenital disorders. We developed a novel Hirschsprung disease (HSCR) mouse model, allowing targeted mutation correction using Cre-loxP system. Crossbreeding with Phox2b-CreERT2 mice enabled removal the causative mutation in vagal neural crest-derived enteric nervous system (ENS) stem cells at various developmental stages (embryonic day 10.5 (E10.5), E11.5, and E12.5). Removal of the causative mutation results in the rescue of the ENS phenotype, preventing aganglionosis in newborns. Similar rescue effects were observed in Schwann cell precursors. Rescued stem cells migrated to tissue defects, differentiating into enteric neurons, contributing tissue repair. Proliferation assays revealed rescued stem cells' enhanced capacity, compensating for low activity in non-rescued cells, thus aiding enteric neurogenesis.
|
