Bone marrow stromal cell transplants prevent experimental enterocolitis and require host CD11b+ splenocytes.
OBJECTIVE
Bone marrow stromal cells (MSCs) are being evaluated as a cellular therapeutic for immune-mediated diseases. We investigated the effects of MSCs in mice with chemically induced colitis and determined the effects of CD11b(+) cells based on the hypothesis that MSCs increase numbers of regulatory T cells.


METHODS
Colitis was induced in mice using trinitrobenzene sulfonic acid; symptoms were monitored as a function of MSC delivery. An immunomodulatory response was determined by measuring numbers of regulatory T cells in mesenteric lymph nodes. In vitro cocultures were used to assess the interaction of MSCs with regulatory T cells and CD11b(+) cells; findings were supported using near-infrared tracking of MSCs in vivo. We chemically and surgically depleted splenic CD11b(+) cells before colitis was induced with trinitrobenzene sulfonic acid to monitor the effects of MSCs. We adoptively transferred CD11b(+) cells that were cocultured with MSCs into mice with colitis.


RESULTS
Intravenous grafts of MSCs prevented colitis and increased survival times of mice. Numbers of Foxp3(+) regulatory T cells increased in mesenteric lymph nodes in mice given MSCs. MSCs increased the numbers of Foxp3(+) splenocytes in a CD11b(+) cell-dependent manner. Transplanted MSCs colocalized near splenic CD11b(+) cells in vivo. Loss of CD11b(+) cells eliminated the therapeutic effect of MSCs. MSCs increased the anticolitis effects of CD11b(+) cells in mice.


CONCLUSIONS
MSC transplants, delivered by specific parameters, reduce colitis in mice. Interactions between MSC and CD11b(+) regulatory T cells might be used to develop potency assays for MSCs, to identify nonresponders to MSC therapy, and to create new cell grafts that are composed of CD11b(+) cells preconditioned by MSCs.
Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
Biju
B
Parekkadan
Rabi
R
Upadhyay
Joshua
J
Dunham
Yoshiko
Y
Iwamoto
Emiko
E
Mizoguchi
Atsushi
A
Mizoguchi
Ralph
R
Weissleder
Martin L
ML
Yarmush
D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation; D039481:CD11b Antigen / Q000378:metabolism*; D002450:Cell Communication; D058948:Cell Tracking; D018920:Coculture Techniques; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016130:Immunophenotyping; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D010641:Phenotype; D013154:Spleen / Q000276:immunology*; D017154:Stromal Cells / Q000637:transplantation*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid
D039481:CD11b Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D014302:Trinitrobenzenesulfonic Acid