MESENCHYMAL STEM CELLS COMPARED WITH MICROVESICLES-BASED THERAPY IMPACTS IMMUNOCOMPETENT CELLS IN MICE WITH CHRONIC RENAL DISEASE

Mesenchymal stem cells which have both pluripotent and immunoregulatory functions are being actively studied as one of the treatment ways in many fields of medicine, including rehabilitation in nephrology. However, in some articles were dedicated to the treatment of different organic pathology with MSC’s was proved that the only reported effects from the application of MSC’s in regenerative medicine are that, after transplantation to damaged organs, in a paracrine manner they may inhibit apoptosis of cells, promote angiogenesis for a better blood supply, and in some cases stimulate cells that have survived in damaged tissues to proliferate in order to replenish dying tissue fragments. In other words, the pro-reparational functions were due to their paracrine effects without the impact of differentiation. Microvesicles are one of the components of this pro-regenerative effect. And although immunoregulatory action has been shown for MSCs, it remains poorly understood for microvesicles.

The aim of this study was to study the immunoregulatory properties of microvesicles (MSC-MB, MB) in comparison with mesenchymal stem cells (MSC). The experiment was carried out on CBA mice 3-4 months old, a model of glycerol-induced chronic renal failure (CRF) was used. MSCs were obtained from the bone marrow of syngeneic mice of the tibia and femur. MVs were obtained by apoptosis by culturing in a serum-free medium under oxygen deprivation conditions. MSC and MSC-MB were injected into the tail vein of mice; organs were harvested on the 11th day after administration of MSC and MSC-MB.

The state of cellular immunity in mice with chronic renal failure (CRF) after the introduction of mesenchymal stem cells (MSC) and microvesicles derived from them (MSC-MB) on the 11th day of the experiment was assessed by flow cytometry. As a result, there was a decrease in the number of T-regulatory cells CD4⁺ CD25⁺ Foxp3⁺, an increase in the content of CD4⁺ CD44⁺ CD62⁺ and CD8⁺ CD44⁺ CD62⁺ memory T-cells.

The effect of MVs was not significantly different from that of MSC. This may indicate that the therapeutic properties of MSCs are determined to a greater extent, if not completely, by MSC-MB. 

1. Alikhan M.A., Huynh M., Kitching A.R., Ooi J.D. Regulatory T cells in renal disease. Clin. Transl. Immunol., 2018, Vol. 7, no. 1, 1004. doi: 10.1002/cti2.1004.

2. Bonventre J.V., Zuk A. Ischemic acute renal failure: an inflammatory disease? Kidney Int., 2004, Vol. 66, pp. 480-485.

3. Burne M.J., Daniels F., El Ghandour A., Mauiyyedi S., Colvin R.B., O’Donnell M.P., Rabb H. Identification of the CD4( þ) T cell as a major pathogenic factor in ischemic acute renal failure. J. Clin. Invest., 2001, Vol. 108, no. 9, pp. 1283-1290.

4. Goes N., Urmson J., Ramassar V., Halloran P.F. Ischemic acute tubular necrosis induces an extensive local cytokine response: evidence for induction of interferon-, transforming growth factor-1, granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-10. Transplantation, 1995, Vol. 59, no. 4, pp. 565-572.

5. Gupta K.H., Goldufsky J.W., Wood S.J., Tardi N.J., Moorthy G.S., Gilbert D.Z., Zayas J.P., Hahm E., Altintas M.M., Reiser J., Shafikhani S.H. Apoptosis and compensatory proliferation signaling are coupled by CrkIcontaining microvesicles. Dev. Cell, 2017, Vol. 41, no. 6, pp. 674-684.

6. Kamijo-Ikemori A.K., Sugaya T., Matsui K., Yokoyama T., Kimura K. Roles of human liver type fatty acid binding protein in kidney disease clarified using hL-FABP chromosomal transgenic mice. Nephrology, 2011, Vol. 16, no. 6, pp 539-544.

7. Karpman D., Ståhl An-L., Arvidsson I. Extracellular vesicles in renal disease. Nat. Rev. Nephrol., 2017, Vol. 13, no. 9, pp. 545-562.

8. Mause S.F., Weber C. Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ. Res., 2010, Vol. 107, no. 9, pp. 1047-1057.

9. Nauta A.J., Fibbe W.E. Immunomodulatory properties of mesenchymal stromal sells. Blood, 2007, Vol. 110, no. 10, pp. 3499-3506.

10. Rabb H. Immune modulation of acute kidney injury. J. Am. Soc. Nephrol., 2006, Vol. 17, no. 3, pp. 604-606.

11. Ratajczak M.Z., Ratajczak J. Extracellular microvesicles/exosomes: discovery, disbelief, acceptance, and the future? Leukemia, 2020, Vol. 34, pp. 3126-3135.

12. Ratajczak M.Z., Ratajczak D., Pedziwiatr D. Extracellular microvesicles (ExMVs) in cell-to-cell communication: a role of telocytes. Adv. Exp. Med. Biol., 2016, Vol. 913, pp. 41-49.

13. Ryu J.-S., Jeong E.-J., Kim J.-Y., Park S.J., W.S. Ju, Kim C.-H., Kim J.-S., Choo Y.-K. Application of mesenchymal stem cells in inflammatory and fibrotic disease. Int. J. Mol. Sci., 2020, Vol. 21., no. 21, 8366. doi: 10.3390/ijms21218366.

14. Ståhl A., Johanson K., Mossberg M., Kahn R., Karpman D. Exosomes and microvesicles in normal physiology, pathophysiology, and renal diseases. Pediatr. Nephrol., 2019, Vol. 34, no. 1, pp. 11-30.

15. Zager R.A., Jonson A.C., Lund S., Hanson S. Acute renal failure: determinants and characteristics of injuryinduced hyperinflammatory response. Am. J. Physiol. Renal Physiol., 2006, Vol. 291, no. 3, pp. 546-556.