Mature chief cells are cryptic progenitors for metaplasia in the stomach.
OBJECTIVE
Gastric cancer evolves in the setting of a pathologic mucosal milieu characterized by both loss of acid-secreting parietal cells and mucous cell metaplasias. Indeed, mucous cell metaplasia is considered the critical preneoplastic lesion for gastric cancer. Previous investigations have shown that infection of mice with Helicobacter felis or induction of acute parietal cell loss with the drug DMP-777 leads to the emergence of a type of metaplasia designated spasmolytic polypeptide-expressing metaplasia (SPEM). We have hypothesized that SPEM arises from proliferating cells in gland bases, either from a cryptic progenitor cell or by transdifferentiation of mature chief cells.


METHODS
Taking advantage of the chief cell-restricted expression of Mist1-Cre-ER(T2), we used lineage mapping to examine whether SPEM lineages were derived from chief cells in 3 independent models of induction by DMP-777 treatment, L-635 treatment, or H felis infection.


RESULTS
Treatment of mice with L-635 for 3 days led to rapid parietal cell loss, induction of a prominent inflammatory infiltrate, and emergence of SPEM. In all 3 models, SPEM developed, at least in part, from transdifferentiation of chief cells. We further found that acute parietal cell loss in the setting of inflammation (L-635 treatment) led to more rapid induction and expansion of SPEM derived from transdifferentiation of chief cells.


CONCLUSIONS
These studies provide direct evidence by lineage tracing that SPEM evolves from differentiated chief cells. Thus, mature gastric chief cells have the ability to act as cryptic progenitors and reacquire proliferative capacity within the context of mucosal injury and inflammation.
Nam
Ki Taek
KT
Nashville VA Medical Center and the Department of Surgery, Epithelial Biology Center, Nashville, Tennessee, USA.
Lee
Hyuk-Joon
HJ
Sousa
Josane F
JF
Weis
Victoria G
VG
O'Neal
Ryan L
RL
Finke
Paul E
PE
Romero-Gallo
Judith
J
Shi
Guanglu
G
Mills
Jason C
JC
Peek
Richard M
RM
Konieczny
Stephen F
SF
Goldenring
James R
JR
D000208:Acute Disease; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D019872:Chief Cells, Gastric / Q000473:pathology* / Q000502:physiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D005756:Gastritis / Q000382:microbiology / Q000473:pathology* / Q000503:physiopathology; D016481:Helicobacter Infections / Q000473:pathology / Q000503:physiopathology; D044922:Helicobacter felis; D036341:Intercellular Signaling Peptides and Proteins; D007763:Lac Operon / Q000235:genetics; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010295:Parietal Cells, Gastric / Q000473:pathology / Q000502:physiology; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011230:Precancerous Conditions / Q000382:microbiology / Q000473:pathology* / Q000503:physiopathology; D013234:Stem Cells / Q000473:pathology* / Q000502:physiology; D013274:Stomach Neoplasms / Q000382:microbiology / Q000473:pathology* / Q000503:physiopathology
D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C451060:spasmolytic polypeptide