Erythropoietin improves effects of mesenchymal stem cells in an experimental model of sepsis


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Abstract

In the last years several studies have shown that mesenchymal stem cells (MSCs) are able to reduce the systemic inflammatory response and mortality in experimental models of sepsis. As recently found, the surface of MSCs have receptors for erythropoietin (EPO). So we hypothesized that the introduction of EPO together with MSCs may enhance their effect and improve the results of sepsis treatment.

Aim: То evaluate morphologic and immunologic effects of combined treatment with EPO and MSC in an experimental LPS sepsis model in rats.

Methods: 50 Wistar rats were randomized into 5 groups: Group 1 - the healthy controls, Groups 2-5 were intraperitoneally introduced bacterial LPS 20 mg/kg. Two hours after LPS injection animals received the following intravenous treatments: Group 3 - 4xl05 allogeneic MSCs, Group 4 - 8.5 pg of recombinant EPO-beta, Group 5 - MSCs and EPO in the same doses. Surviving animals were euthanased on the 4th day. The morphological study of the liver, spleen, thymus, lungs, kidney tissues was performed. We analyzed the tissue changes, white blood cells count and serum level of IL-lß, IL-2, IL-6, TNF-α.

Results: Mortality in LPS groups did not differ. The highest white blood cells count was found in the group of combined treatment EPO+MSCs (8.15x106 cells/ml) compared with controls (2,15x10s cells/ml) and LPS controls (6,52x10s cells/ml). There were no differences in levels of TNF-α, IL-2 and IL-6 between the groups, but serum IL-1ß level in groups 2 and 4 was significantly higher than in treated with MSCs and MSCc + EPO animals. Histologically in the group 5 we observed significantly less leukocyte lung interalveolar septal infiltration and kidney tubular dystrophy. The most significant differences in group LPS + EPO were found in the lymphoid tissue - considerable hyperplasia of spleen white pulp and thymus cortex, whereas in the other groups different degrees of atrophy of the corresponding zones were noted.

Conclusions: Combined treatment with EPO and MSCs can reduce acute lung injury and kidney damage, cause hyperplasia of lymphoid tissue and enhance the immune response more than separate treatment in an experimental model of sepsis in rats.

About the authors

Alexandr V. Averyanov

Federal Scientific and Clinical Center for Specialized Types of Medical Care and Medical Technologies FMBA of Russia

Author for correspondence.
Email: averyanovav@mail.ru

Deputy General Director for Research and Medical Technologies, Doctor of Medical Sciences

Russian Federation, Moscow

Anatolyi G. Konoplyannikov

Medical Radiological Research Center of the Ministry of Health and Social Development of Russia

Email: konopl@obninsk.ru

Head of the Department of Cellular and Experimental Radiation Therapy, Professor, Doctor of Biological Sciences

Russian Federation, Obninsk

Fedor G. Zabozlaev

Federal Scientific and Clinical Center for Specialized Types of Medical Care and Medical Technologies FMBA of Russia

Email: fzab@mail.ru

Head of the Pathological Department, Doctor of Medical Sciences, Professor

Russian Federation, Moscow

Anastasyi S. Sorokina

Federal Scientific and Clinical Center for Specialized Types of Medical Care and Medical Technologies FMBA of Russia

Email: averyanovav@mail.ru

laboratory assistant of the pathological and anatomical department

Russian Federation, Moscow

Dmitryi A. Akulshin

Federal Scientific and Clinical Center for Specialized Types of Medical Care and Medical Technologies FMBA of Russia

Email: averyanovav@mail.ru

head of the clinical diagnostic laboratory

Russian Federation, Moscow

Oleg P. Kuzovlev

Federal Scientific and Clinical Center for Specialized Types of Medical Care and Medical Technologies FMBA of Russia

Email: averyanovav@mail.ru

General Director, Doctor of Medicine, Professor

Russian Federation, Moscow

Natalia V. Kukailo

Federal Scientific and Clinical Center for Specialized Types of Medical Care and Medical Technologies FMBA of Russia

Email: averyanovav@mail.ru

Clinical Diagnostic Laboratory Doctor

Russian Federation, Moscow

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Supplementary files

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2. Fig. 1. Study design

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3. Fig. 2. White blood cell count

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4. Fig. 4 Representative micrograph of thymus tissue 72 hours after administration of lipopolysaccharide (hematoxylin-eosin x100).

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Copyright (c) 2021 Averyanov A.V., Konoplyannikov A.G., Zabozlaev F.G., Sorokina A.S., Akulshin D.A., Kuzovlev O.P., Kukailo N.V.

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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

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