PMID- 19956666
OWN - NLM
STAT- MEDLINE
DCOM- 20100426
LR  - 20220316
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 4
IP  - 11
DP  - 2009 Nov 24
TI  - Protective role of R-spondin1, an intestinal stem cell growth factor, against 
      radiation-induced gastrointestinal syndrome in mice.
PG  - e8014
LID - 10.1371/journal.pone.0008014 [doi]
LID - e8014
AB  - BACKGROUND: Radiation-induced gastrointestinal syndrome (RIGS) results from a 
      combination of direct cytocidal effects on intestinal crypt and endothelial cells 
      and subsequent loss of the mucosal barrier, resulting in electrolyte imbalance, 
      diarrhea, weight loss, infection and mortality. Because R-spondin1 (Rspo1) acts 
      as a mitogenic factor for intestinal stem cells, we hypothesized that systemic 
      administration of Rspo1 would amplify the intestinal crypt cells and accelerate 
      the regeneration of the irradiated intestine, thereby, ameliorating RIGS. METHODS 
      AND FINDINGS: Male C57Bl/6 mice received recombinant adenovirus expressing human 
      R-spondin1 (AdRspo1) or E.coli Lacz (AdLacz), 1-3 days before whole body 
      irradiation (WBI) or abdominal irradiation (AIR). Post-irradiation survival was 
      assessed by Kaplan Meier analysis. RIGS was assessed by histological examination 
      of intestine after hematoxilin and eosin staining, immunohistochemical staining 
      of BrdU incorporation, Lgr5 and beta-catenin expression and TUNEL staining. The 
      xylose absorption test (XAT) was performed to evaluate the functional integrity 
      of the intestinal mucosal barrier. In order to examine the effect of R-spondin1 
      on tumor growth, AdRspo1 and AdLacZ was administered in the animals having 
      palpable tumor and then exposed to AIR. There was a significant increase in 
      survival in AdRspo1 cohorts compared to AdLacZ (p<0.003) controls, following WBI 
      (10.4 Gy). Significant delay in tumor growth was observed after AIR in both 
      cohorts AdRspo1 and AdLacZ but AdRspo1 treated animals showed improved survival 
      compared to AdLacZ. Histological analysis and XAT demonstrated significant 
      structural and functional regeneration of the intestine in irradiated animals 
      following AdRspo1 treatment. Immunohistochemical analysis demonstrated an 
      increase in Lgr5+ve crypt cells and the translocation of beta-catenin from the 
      cytosol to nucleus and upregulation of beta-catenin target genes in 
      AdRspo1-treated mice, as compared to AdLacz-treated mice. CONCLUSION: Rspo1 
      promoted radioprotection against RIGS and improved survival of mice exposed to 
      WBI. The mechanism was likely related to induction of the Wnt-beta-catenin 
      pathway and promotion of intestinal stem cell regeneration. Rspo1 has protective 
      effect only on normal intestinal tissue but not in tumors after AIR and thereby 
      may increase the therapeutic ratio of chemoradiation therapy in patients 
      undergoing abdominal irradiation for GI malignancies.
FAU - Bhanja, Payel
AU  - Bhanja P
AD  - Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New 
      York, United States of America.
FAU - Saha, Subhrajit
AU  - Saha S
FAU - Kabarriti, Rafi
AU  - Kabarriti R
FAU - Liu, Laibin
AU  - Liu L
FAU - Roy-Chowdhury, Namita
AU  - Roy-Chowdhury N
FAU - Roy-Chowdhury, Jayanta
AU  - Roy-Chowdhury J
FAU - Sellers, Rani S
AU  - Sellers RS
FAU - Alfieri, Alan A
AU  - Alfieri AA
FAU - Guha, Chandan
AU  - Guha C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091124
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (RSPO1 protein, mouse)
RN  - 0 (Thrombospondins)
RN  - 0 (beta Catenin)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Cell Line, Tumor
MH  - DNA Damage
MH  - Dose-Response Relationship, Radiation
MH  - Gastrointestinal Diseases/etiology/*metabolism
MH  - Intercellular Signaling Peptides and Proteins/*metabolism
MH  - Intestinal Mucosa/metabolism
MH  - Intestines/cytology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Radiation Injuries
MH  - Stem Cells/cytology/*metabolism
MH  - Thrombospondins/blood/*physiology
MH  - beta Catenin/metabolism
PMC - PMC2777375
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2009/12/04 06:00
MHDA- 2010/04/27 06:00
PMCR- 2009/11/24
CRDT- 2009/12/04 06:00
PHST- 2009/08/28 00:00 [received]
PHST- 2009/10/26 00:00 [accepted]
PHST- 2009/12/04 06:00 [entrez]
PHST- 2009/12/04 06:00 [pubmed]
PHST- 2010/04/27 06:00 [medline]
PHST- 2009/11/24 00:00 [pmc-release]
AID - 09-PONE-RA-012537 [pii]
AID - 10.1371/journal.pone.0008014 [doi]
PST - epublish
SO  - PLoS One. 2009 Nov 24;4(11):e8014. doi: 10.1371/journal.pone.0008014.