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Mouse bone marrow-derived mesenchymal stem cells inhibit leukemia/lymphoma cell proliferation in vitro and in a mouse model of allogeneic bone marrow transplant.

Song N, Gao L, Qiu H, Huang C, Cheng H, Zhou H, Lv S, Chen L, Wang J - Int. J. Mol. Med. (2015)

Bottom Line: Cell proliferation, apoptosis, cell cycle progression and the amount of cytokine secretion were then measured using a Cell Counting kit‑8, Annexin V/propidium iodide staining, flow cytometry and ELISA, respectively.Our results revealed that the MSCs inhibited the proliferation of the mouse lymphoma and leukemia cells in vitro, leading to cell cycle arrest and reducing the secretion of interleukin (IL)‑10.The results from the present study indicate that MSCs may be safe and effective when used in allogeneic BMT for the treatment of hemotological malignancies.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Institute of Hematology, PLA, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China.

ABSTRACT
The allogeneic hematopoietic stem cell (HSC) transplantation of mesenchymal stem cells (MSCs) contributes to the reconstitution of hematopoiesis by ameliorating acute graft‑versus‑host disease (aGVHD). However, the role of MSCs in graft‑versus‑leukemia remains to be determined. In the present study, we co‑cultured C57BL/6 mouse bone marrow (BM)‑derived MSCs with A20 murine B lymphoma, FBL3 murine erythroleukemia and P388 murine acute lymphocytic leukemia cells. Cell proliferation, apoptosis, cell cycle progression and the amount of cytokine secretion were then measured using a Cell Counting kit‑8, Annexin V/propidium iodide staining, flow cytometry and ELISA, respectively. We also established a model of allogeneic bone marrow transplantation (BMT) using BALB/c mice. Following the administration of A20 cells and MSCs, we recorded the symptoms and the survival of the mice for 4 weeks, assessed the T cell subsets present in peripheral blood, and, after the mice were sacrifice, we determined the infiltration of MSCs into the organs by histological staining. Our results revealed that the MSCs inhibited the proliferation of the mouse lymphoma and leukemia cells in vitro, leading to cell cycle arrest and reducing the secretion of interleukin (IL)‑10. In our model of allogeneic BMT, the intravenous injection of MSCs into the mice injected wth A20 cells decreased the incidence of lymphoma, improved survival, increased the fraction of CD3+CD8+ T cells, decreased the fraction of CD3+CD4+ T cells and CD4+CD25+ T cells in peripheral blood, and ameliorated the manifestation of aGVHD. The results from the present study indicate that MSCs may be safe and effective when used in allogeneic BMT for the treatment of hemotological malignancies.

No MeSH data available.


Related in: MedlinePlus

Mesenchymal stem cells (MSCs) increase the weight and extend the survival of mice in a model of allogeneic bone marrow transplantation (BMT). (A) Mice were weighed following BMT, and the mean wild-type curves ± SEM were established for the mice receiving PBS (–, n=10), bone marrow (BM) cells alone (−, n=10), BM cells supplemented with MSCs (×, n=10), BM cells plus A20 cells (◻, n=17), or BM cells with A20 cells plus MSCs (■, n=17). (B and C) Results are represented as a Kaplan-Meier survival curve. (B) There was significant difference between the PBS group and the other 2 groups (BM and BM-MSC group) (P<0.01). (C) Lethally irradiated BABL/c mice were transplanted with 1×107 BM cells and 1×104 A20 cells with or without 5×105 MSCs. The survival rate in the 2 groups was not significant, but the the time of death of the mice injected with MSCs and A20 cells was delayed.
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f5-ijmm-36-01-0139: Mesenchymal stem cells (MSCs) increase the weight and extend the survival of mice in a model of allogeneic bone marrow transplantation (BMT). (A) Mice were weighed following BMT, and the mean wild-type curves ± SEM were established for the mice receiving PBS (–, n=10), bone marrow (BM) cells alone (−, n=10), BM cells supplemented with MSCs (×, n=10), BM cells plus A20 cells (◻, n=17), or BM cells with A20 cells plus MSCs (■, n=17). (B and C) Results are represented as a Kaplan-Meier survival curve. (B) There was significant difference between the PBS group and the other 2 groups (BM and BM-MSC group) (P<0.01). (C) Lethally irradiated BABL/c mice were transplanted with 1×107 BM cells and 1×104 A20 cells with or without 5×105 MSCs. The survival rate in the 2 groups was not significant, but the the time of death of the mice injected with MSCs and A20 cells was delayed.

Mentions: MSCs have been reported to both promote (15) and abrogate (5) tumor growth in vivo. In this study, in order to investigate the effect of MSCs in a model of allogeneic BMT, we implanted A20 B lymphoma cells into mice. Lethally irradiated BABL/c female mice were either injected with PBS (n=10), grafted with 1×107 B6 BM cells (n=10), 1×107 donor BM cells and 5×105 MSCs (n=10); 1×107 donor BM cells and 1×104 A20 cells (n=17); or 1×107 donor BM cells, 1×104 A20 cells and 5×105 MSCs (n=17). Ninety percent of the grafted mice in the BM group and 100% in the BM-MSC group survived for >28 days, while the ungrafted animals died before day 21 (Fig. 5B). When 1×104 A20 cells were injected, the mice in the BM group exhibited a characteristic infiltration of leukemia/lymphoma cells presenting as paralysis and splenohepatomegalia. The mice administered the A20 and MSCs did not exhibit paralysis, but exhibited mild splenohepatomegalia. The mice injected with A20 cells also exhibited a hunched posture, dull fur and slight diarrhea, and the histological examination revealed necrosis, defluxion, vacuolar degeneration of the small intestinal mucosa, and atrophy and collapse in the alveolae. These symptoms were less severe in the mice that also received MSCs (Fig. 6), and the mean body weight was significantly higher in the mice that received MSCs in addition to A20 cells from 8 days after irradiation (Fig. 5A). Excluding those mice that died of complications associated with irradiation, the mice administered the A20 cells and MSCs survived longer than the mice administered only A20 cells (Fig. 5C).


Mouse bone marrow-derived mesenchymal stem cells inhibit leukemia/lymphoma cell proliferation in vitro and in a mouse model of allogeneic bone marrow transplant.

Song N, Gao L, Qiu H, Huang C, Cheng H, Zhou H, Lv S, Chen L, Wang J - Int. J. Mol. Med. (2015)

Mesenchymal stem cells (MSCs) increase the weight and extend the survival of mice in a model of allogeneic bone marrow transplantation (BMT). (A) Mice were weighed following BMT, and the mean wild-type curves ± SEM were established for the mice receiving PBS (–, n=10), bone marrow (BM) cells alone (−, n=10), BM cells supplemented with MSCs (×, n=10), BM cells plus A20 cells (◻, n=17), or BM cells with A20 cells plus MSCs (■, n=17). (B and C) Results are represented as a Kaplan-Meier survival curve. (B) There was significant difference between the PBS group and the other 2 groups (BM and BM-MSC group) (P<0.01). (C) Lethally irradiated BABL/c mice were transplanted with 1×107 BM cells and 1×104 A20 cells with or without 5×105 MSCs. The survival rate in the 2 groups was not significant, but the the time of death of the mice injected with MSCs and A20 cells was delayed.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494598&req=5

f5-ijmm-36-01-0139: Mesenchymal stem cells (MSCs) increase the weight and extend the survival of mice in a model of allogeneic bone marrow transplantation (BMT). (A) Mice were weighed following BMT, and the mean wild-type curves ± SEM were established for the mice receiving PBS (–, n=10), bone marrow (BM) cells alone (−, n=10), BM cells supplemented with MSCs (×, n=10), BM cells plus A20 cells (◻, n=17), or BM cells with A20 cells plus MSCs (■, n=17). (B and C) Results are represented as a Kaplan-Meier survival curve. (B) There was significant difference between the PBS group and the other 2 groups (BM and BM-MSC group) (P<0.01). (C) Lethally irradiated BABL/c mice were transplanted with 1×107 BM cells and 1×104 A20 cells with or without 5×105 MSCs. The survival rate in the 2 groups was not significant, but the the time of death of the mice injected with MSCs and A20 cells was delayed.
Mentions: MSCs have been reported to both promote (15) and abrogate (5) tumor growth in vivo. In this study, in order to investigate the effect of MSCs in a model of allogeneic BMT, we implanted A20 B lymphoma cells into mice. Lethally irradiated BABL/c female mice were either injected with PBS (n=10), grafted with 1×107 B6 BM cells (n=10), 1×107 donor BM cells and 5×105 MSCs (n=10); 1×107 donor BM cells and 1×104 A20 cells (n=17); or 1×107 donor BM cells, 1×104 A20 cells and 5×105 MSCs (n=17). Ninety percent of the grafted mice in the BM group and 100% in the BM-MSC group survived for >28 days, while the ungrafted animals died before day 21 (Fig. 5B). When 1×104 A20 cells were injected, the mice in the BM group exhibited a characteristic infiltration of leukemia/lymphoma cells presenting as paralysis and splenohepatomegalia. The mice administered the A20 and MSCs did not exhibit paralysis, but exhibited mild splenohepatomegalia. The mice injected with A20 cells also exhibited a hunched posture, dull fur and slight diarrhea, and the histological examination revealed necrosis, defluxion, vacuolar degeneration of the small intestinal mucosa, and atrophy and collapse in the alveolae. These symptoms were less severe in the mice that also received MSCs (Fig. 6), and the mean body weight was significantly higher in the mice that received MSCs in addition to A20 cells from 8 days after irradiation (Fig. 5A). Excluding those mice that died of complications associated with irradiation, the mice administered the A20 cells and MSCs survived longer than the mice administered only A20 cells (Fig. 5C).

Bottom Line: Cell proliferation, apoptosis, cell cycle progression and the amount of cytokine secretion were then measured using a Cell Counting kit‑8, Annexin V/propidium iodide staining, flow cytometry and ELISA, respectively.Our results revealed that the MSCs inhibited the proliferation of the mouse lymphoma and leukemia cells in vitro, leading to cell cycle arrest and reducing the secretion of interleukin (IL)‑10.The results from the present study indicate that MSCs may be safe and effective when used in allogeneic BMT for the treatment of hemotological malignancies.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Institute of Hematology, PLA, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China.

ABSTRACT
The allogeneic hematopoietic stem cell (HSC) transplantation of mesenchymal stem cells (MSCs) contributes to the reconstitution of hematopoiesis by ameliorating acute graft‑versus‑host disease (aGVHD). However, the role of MSCs in graft‑versus‑leukemia remains to be determined. In the present study, we co‑cultured C57BL/6 mouse bone marrow (BM)‑derived MSCs with A20 murine B lymphoma, FBL3 murine erythroleukemia and P388 murine acute lymphocytic leukemia cells. Cell proliferation, apoptosis, cell cycle progression and the amount of cytokine secretion were then measured using a Cell Counting kit‑8, Annexin V/propidium iodide staining, flow cytometry and ELISA, respectively. We also established a model of allogeneic bone marrow transplantation (BMT) using BALB/c mice. Following the administration of A20 cells and MSCs, we recorded the symptoms and the survival of the mice for 4 weeks, assessed the T cell subsets present in peripheral blood, and, after the mice were sacrifice, we determined the infiltration of MSCs into the organs by histological staining. Our results revealed that the MSCs inhibited the proliferation of the mouse lymphoma and leukemia cells in vitro, leading to cell cycle arrest and reducing the secretion of interleukin (IL)‑10. In our model of allogeneic BMT, the intravenous injection of MSCs into the mice injected wth A20 cells decreased the incidence of lymphoma, improved survival, increased the fraction of CD3+CD8+ T cells, decreased the fraction of CD3+CD4+ T cells and CD4+CD25+ T cells in peripheral blood, and ameliorated the manifestation of aGVHD. The results from the present study indicate that MSCs may be safe and effective when used in allogeneic BMT for the treatment of hemotological malignancies.

No MeSH data available.


Related in: MedlinePlus