Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jan 29:8:10.
doi: 10.3389/fcell.2020.00010. eCollection 2020.

Impact of Mesenchymal Stromal Cells and Their Extracellular Vesicles in a Rat Model of Kidney Rejection

Maria Jose Ramirez-Bajo  1   2 , Jordi Rovira  1   2 , Marta Lazo-Rodriguez  3 , Elisenda Banon-Maneus  2   3 , Valeria Tubita  1 , Daniel Moya-Rull  1   2 , Natalia Hierro-Garcia  2   3 , Pedro Ventura-Aguiar  4 , Federico Oppenheimer  4 , Josep M Campistol  2   3   4 , Fritz Diekmann  1   2   4
Affiliations

Impact of Mesenchymal Stromal Cells and Their Extracellular Vesicles in a Rat Model of Kidney Rejection

Maria Jose Ramirez-Bajo et al. Front Cell Dev Biol. .

Abstract

Background: Mesenchymal stromal cells (MSCs) from different sources possess great therapeutic potential due to their immunomodulatory properties associated with allograft tolerance. However, a crucial role in this activity resides in extracellular vesicles (EVs) and signaling molecules secreted by cells. This study aimed to evaluate the immunomodulatory properties of donor and recipient MSCs isolated from adipose tissue (AD) or bone marrow (BM) and their EVs on kidney outcome in a rat kidney transplant model.

Methods: The heterotopic-kidney-transplant Fisher-to-Lewis rat model (F-L) was performed to study mixed cellular and humoral rejection. After kidney transplantation, Lewis recipients were assigned to 10 groups; two control groups; four groups received autologous MSCs (either AD- or BM- MSC) or EVs (derived from both cell types); and four groups received donor-derived MSCs or EVs. AD and BM-EVs were purified by ultracentrifugation. Autologous cell therapies were administered three times intravenously; immediately after kidney transplantation, 4 and 8 weeks, whereas donor-derived cell therapies were administered once intravenously immediately after transplantation. Survival and renal function were monitored. Twelve weeks after kidney transplantation grafts were harvested, infiltrating lymphocytes were analyzed by flow cytometry and histological lesions were characterized.

Results: Autologous AD- and BM-MSCs, but not their EVs, prolonged graft and recipient survival in a rat model of kidney rejection. Autologous AD- and BM-MSCs significantly improved renal function during the first 4 weeks after transplantation. The amelioration of graft function could be associated with an improvement in tubular damage, as well as in T, and NK cell infiltration. On the other side, the application of donor-derived AD-MSC was harmful, and all rats died before the end of the protocol. AD-EVs did not accelerate the rejection. Contrary to autologous MSCs results, the single dose of donor-derived BM-MSCs is not enough to ameliorate kidney graft damage.

Conclusion: EVs treatments did not exert any benefit in our experimental settings. In the autologous setting, BM-MSCs prompted as a potentially promising therapy to improve kidney graft outcomes in rats with chronic mixed rejection. In the donor-derived setting, AD-MSC accelerated progression to end-stage kidney disease. Further experiments are required to adjust timing and dose for better long-term outcomes.

Keywords: adipose tissue; bone marrow; chronic kidney disease; extracellular vesicles; immunomodulation; kidney transplantation; mesenchymal stromal cells.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Experimental design of the protocol of AD- and BM-MSCs and their EVs administration regimens from recipient and donor in the Fisher-Lewis renal transplant model. (A) Cell therapies from recipients were administered intravenously in the moment of the transplant, and 4 and 8 weeks post-transplant. (B) Cell therapies from the donor were administrated once after kidney transplantation. KTx, kidney transplantation; UniNx, right uninephrectomy; AD, adipose tissue-derived; BM, bone marrow; MSC, mesenchymal stromal cells; EVs, extracellular vesicles.
FIGURE 2
FIGURE 2
Effect of autologous AD- or BM-MSCs and their EVs treatments on renal function and rat survival after kidney transplantation. (A) Blood Urea Nitrogen. (B) Blood creatinine levels. (C) Proteinuria. (D) Urine creatinine levels. (E) Survival curve was generated using the Kaplan-Meier method and compared using the long-rank (Mantel-Cox) test. (F) Mean survival time (days). *Significantly different when compared L-L vs F-L + Ø group (*P < 0.05; **P < 0.01; and ***P < 0.001). #F-L + Ø group vs BM-MSCF (#P < 0.05).
FIGURE 3
FIGURE 3
Histological evaluation of lesions observed in renal allograft during the rejection process after autologous AD-, BM-MSCs and their EVs treatments. (A) Tubular atrophy, (B) fibrosis, (C) tubulitis, (D) capillaritis, and (E) interstitial infiltrate in rats without treatment (Ø) and with the administration of AD-, BM-MSC, and their EVs. Significantly different when compared to F-L + Ø group (*P < 0.05).
FIGURE 4
FIGURE 4
Effect of autologous AD- and BM-MSCs and their EVs treatments on infiltrating immune cell in kidney graft. (A) T cells, CD3+. (B) Thelpers + Treg cells, CD3+CD4+. (C) Tcytotoxic cells, CD3+CD8+. (D) NK cells, CD3–CD314+CD161+. (E) B cells, CD3–CD161–B220+. *Significantly different when compared to F-L + Ø group (*P < 0.05; **P < 0.01).
FIGURE 5
FIGURE 5
Effect of donor-derived AD- or BM-MSCs and their EVs treatments on renal function and rat survival after kidney transplantation. (A) Blood Urea Nitrogen. (B) Blood creatinine levels. (C) Proteinuria. (D) Urine creatinine levels. (E) Survival curve was generated using the Kaplan-Meier method and compared using the long-rank (Mantel-Cox) test. (F) Mean survival time (days). *Significantly different when compared L-L vs F-L + Ø group (*P < 0.05; **P < 0.01, and ***P < 0.001). #F-L + Ø group vs BM-MSCF (#P < 0.05). &F-L + Ø group vs BM-EVF (&P < 0.05). [dollar]F-L + Ø group vs AD-MSCF ([dollar]P < 0.05).
FIGURE 6
FIGURE 6
Histological evaluation of lesions observed in renal allograft during the rejection process after donor-derived BM-MSCs, their EVs and AD-EVs treatments. (A) Tubular atrophy, (B) fibrosis, (C) tubulitis, (D) capillaritis, and (E) interstitial infiltrate in rats without treatment (Ø) and with treatment. Significantly different when compared to F-L + Ø group (*P < 0.05).
FIGURE 7
FIGURE 7
Effect of donor-derived AD- and BM-MSCs and their EVs treatments on infiltrating immune cell in kidney graft. (A) T cells, CD3+. (B) Thelpers + Treg cells, CD3+CD4+. (C) Tcytotoxic cells, CD3+CD8+. (D), NK cells, CD3–CD314+CD161+. (E) B cells, CD3–CD161–B220+. ∗Significantly different when compared to F-L + Ø group (*P < 0.05; **P < 0.01).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Alvaro-Gracia J. M., Jover J. A., Garcia-Vicuna R., Carreno L., Alonso A., Marsal S., et al. (2017). Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial. Ann. Rheum. Dis. 76 196–202. 10.1136/annrheumdis-2015-208918 - DOI - PubMed
    1. Ammar H. I., Sequiera G. L., Nashed M. B., Ammar R. I., Gabr H. M., Elsayed H. E., et al. (2015). Comparison of adipose tissue- and bone marrow- derived mesenchymal stem cells for alleviating doxorubicin-induced cardiac dysfunction in diabetic rats. Stem Cell Res. Ther. 6:148. 10.1186/s13287-015-0142-x - DOI - PMC - PubMed
    1. Bartholomew A., Sturgeon C., Siatskas M., Ferrer K., McIntosh K., Patil S., et al. (2002). Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp. Hematol. 30 42–48. 10.1016/s0301-472x(01)00769-x - DOI - PubMed
    1. Ben-Ami E., Miller A., Berrih-Aknin S. (2014). T cells from autoimmune patients display reduced sensitivity to immunoregulation by mesenchymal stem cells: role of IL-2. Autoimmun. Rev. 13 187–196. 10.1016/j.autrev.2013.09.007 - DOI - PubMed
    1. Blazquez R., Sanchez-Margallo F. M., de la Rosa O., Dalemans W., Alvarez V., Tarazona R., et al. (2014). Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells. Front. Immunol. 5:556. 10.3389/fimmu.2014.00556 - DOI - PMC - PubMed

LinkOut - more resources

  NODES
admin 8
twitter 2