The use of mesenchymal stem cells in the complex treatment of drug-resistant kidney tuberculosis (experimental study with morphological control)

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Abstract

Introduction. The use of mesenchymal stem cells (MSCs) is recognized as a promising direction for the treatment of diseases with a predominance of inflammation and sclerosis in the pathogenesis, which includes nephrotuberculosis (NT).

Target. Studying the effectiveness of using MSCs in the complex treatment of experimental renal tuberculosis caused by a multidrug-resistant pathogen strain, and assessing the effect of cell therapy on the nature of reparative processes.

Material and methods. NT with MDR was modeled in rabbits by inoculating the renal parenchyma cortex with a suspension of the clinical strain 5582 of Mycobacterium tuberculosis genotype Beijing (106 mycobacteria/0.2 ml). There were 3 groups: 1st (n=6) – infection control (infected, untreated); 2nd (n=7) – anti-tuberculosis therapy – ethambutol, bedaquiline, perchlozone, linezolid; 3rd main group (n=7) – rabbits 2 months after the start of chemotherapy were injected with a single suspension of 5×107 MSCs/2 ml PBS into the lateral vein of the ear. NT was confirmed by the results of Diaskintest® and computed tomography (CT), and the presence of viable MSCs by confocal microscopy with RKN-26 dye. A histological and morphometric study of the kidneys was carried out. We used the Statistica 7.0 package

Results. The development of NT was confirmed by positive results of Diaskintest® and CT data (18 and 30 days after infection, respectively). 3 months after infection, only in group 1, foci of specific inflammation remained in the kidney tissue and pronounced glomerular changes were noted. In rabbits of the 3rd group, compared to the 2nd group, a low width of the medulla was revealed, as well as parameters of the area of interstitial fibrosis and collagen area, and higher values of glomerular cellularity.

Conclusion. The participation of MSCs in complex therapy of NT led to a complete regression of specific inflammation in the kidney tissues, acceleration of reparative processes, and contributed to the preservation of the filtration capacity of the kidneys and the efficiency of urine excretion.

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About the authors

Tatyana I. Vinogradova

FGBU “St. Petersburg Research Institute of Phthisiopulmonology” of the Ministry of Health of Russia

Author for correspondence.
Email: vinogradova@spbniif.ru
ORCID iD: 0000-0002-5234-349X

Head of the Research Laboratory of Experimental Medicine, Doctor of Medical Sciences, Professor

Russian Federation, Ligovsky Ave., 2–4, St. Petersburg, 191036

Dilyara S. Esmedlyayeva

FGBU “St. Petersburg Research Institute of Phthisiopulmonology” of the Ministry of Health of Russia

Email: diljara-e@yandex.ru
ORCID iD: 0000-0002-9841-0061

Senior Researcher of the Research Laboratory of Microbiology, Biochemistry and Immunogenetics, Candidate of Biological Sciences

Russian Federation, Ligovsky Ave., 2–4, St. Petersburg, 191036

Marina E. Dyakova

FGBU “St. Petersburg Research Institute of Phthisiopulmonology” of the Ministry of Health of Russia

Email: marinadyakova@yandex.ru
ORCID iD: 0000-0002-7810-880X

Senior Researcher of the Research Laboratory of Microbiology, Biochemistry and Immunogenetics, Doctor of Biological Sciences

Russian Federation, Ligovsky Ave., 2–4, St. Petersburg, 191036

Alexander N. Muravyev

FGBU “St. Petersburg Research Institute of Phthisiopulmonology” of the Ministry of Health of Russia

Email: urolog5@gmail.com
ORCID iD: 0000-0002-6974-5305

Scientific Secretary, Candidate of Medical Sciences

Russian Federation, Ligovsky Ave., 2–4, St. Petersburg, 191036

Anna N. Remezova

FGBU “St. Petersburg Research Institute of Phthisiopulmonology” of the Ministry of Health of Russia

Email: urolog-remezovaanna@yandex.ru
ORCID iD: 0000-0001-8145-4159

Postgraduate Student

Russian Federation, Ligovsky Ave., 2–4, St. Petersburg, 191036

Boris M. Ariel

FGBU “St. Petersburg Research Institute of Phthisiopulmonology” of the Ministry of Health of Russia

Email: arielboris@rambler.ru
ORCID iD: 0000-0002-7243-8621

Advisor to the Director, Doctor of Medical Sciences, Professor

Russian Federation, Ligovsky Ave., 2–4, St. Petersburg, 191036

Evdokia O. Bogdanova

FGBU “St. Petersburg Research Institute of Phthisiopulmonology” of the Ministry of Health of Russia

Email: evdokia.bogdanova@gmail.com
ORCID iD: 0000-0003-1969-1959

Senior Researcher, Research Laboratory of Morphology, Candidate of Biological Sciences

Russian Federation, Ligovsky Ave., 2–4, St. Petersburg, 191036

Marine Z. Dogonadze

FGBU “St. Petersburg Research Institute of Phthisiopulmonology” of the Ministry of Health of Russia

Email: marine-md@mail.ru
ORCID iD: 0000-0002-9161-466X

Senior Researcher of the Research Laboratory of Microbiology, Biochemistry and Immunogenetics, Candidate of Biological Sciences

Russian Federation, Ligovsky Ave., 2–4, St. Petersburg, 191036

Natalya V. Zabolotnykh

FGBU “St. Petersburg Research Institute of Phthisiopulmonology” of the Ministry of Health of Russia

Email: zabol-natal@yandex.ru
ORCID iD: 0000-0002-2946-2415

Leading Researcher of the Research Laboratory of Experimental Medicine, Doctor of Medical Sciences

Russian Federation, Ligovsky Ave., 2–4, St. Petersburg, 191036

Natalia M. Yudintseva

FGBUN Institute of Cytology of the Russian Academy of Sciences

Email: yudintceva@mail.ru
ORCID iD: 0000-0002-7357-1571

Leading Researcher, Center for Cellular Technologies, Candidate of Biological Sciences

Russian Federation, Tikhoretsky pr., 4, St. Petersburg, 194064

Victoria O. Polyakova

FGBU “St. Petersburg Research Institute of Phthisiopulmonology” of the Ministry of Health of Russia

Email: vo.polyakova@spbniif.ru
ORCID iD: 0000-0001-8682-9909

Deputy Director, Doctor of Biological Sciences, Professor

Russian Federation, Ligovsky Ave., 2–4, St. Petersburg, 191036

Petr K. Yablonskiy

FGBU “St. Petersburg Research Institute of Phthisiopulmonology” of the Ministry of Health of Russia; St. Petersburg State University

Email: piotr_yablonskii@mail.ru
ORCID iD: 0000-0003-4385-9643

Director of the St. Petersburg Research Institute of Phthisiopulmonology of the Ministry of Health of the Russian Federation; First Vice-Rector for Medical Activities of St. Petersburg State University, Doctor of Medical Sciences, Professor

Russian Federation, Ligovsky Ave., 2–4, St. Petersburg, 191036; Universitetskaya nab., 7/9, St. Petersburg, 199034

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2. Fig. 1. Assessment of rabbit PKH-26MSC internalization: a – confocal microscopy image of MSCs co-incubated with SPION (150 μg/ml) for 24 hours; б – control (untreated cells). Nuclei were stained with DAPI (arrow with dashes). SPIONs were detected by reflected laser scanning (white arrow). Scale bars, 100 µm

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3. Fig. 2. CT scan of the abdominal cavity: a – a clearly defined area of reduced perfusion is identified in the left kidney (arrow with dashes indicates low blood flow compared to the remaining parenchyma (white arrow));б – focus of destruction (hypovascular zone)

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4. Fig. 3. Histological changes in the kidneys of rabbits in the study groups: a – specific inflammation in group 1 (infection control), lymphocytic infiltration: б, в – absence of inflammatory changes, respectively, in the treatment control group (anti-tuberculosis therapy, anti-tuberculosis therapy) and in the combination therapy group (anti-tuberculosis therapy) +MSK); г – acid-fast mycobacteria in areas of specific inflammation in group 1; (a–в – hematoxylin and eosin staining; magnification, ×400; г– Ziehl–Neelsen staining; magnification, ×1000)

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5. Fig. 4. Microphotographs of the kidneys of rabbits of groups 2 and 3: a – group 2, lymphocytic and macrophage infiltration with tubular atrophy, protein casts; б – group 3, lymphocytic and macrophage infiltration with tubular atrophy, protein casts and stromal remodeling; (staining with hematoxylin and eosin; magnification ×200)

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6. Fig. 5. Microphotographs of the kidneys of rabbits of the 3rd group. Confocal microscopy of cryosections of kidney tissue: a – accumulation of MSCs labeled with SPIONs in the kidneys 1 month after systemic administration; б – control (healthy rabbit without injection of SPIONs). Nuclei were stained with DAPI (dash arrow), SPIONs were detected by reflected laser scanning (white arrow); scale bars, 100 µm. Light microscopy: в – Perls-positive inclusions (Perls staining; magnification ×1000)

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7. Fig. 6. Microphotographs of the glomeruli of the left (infected) kidneys of rabbits of the studied groups: a – group 1;б – group 2; в – group 3 (staining with hematoxylin and eosin; magnification ×400)

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8. Fig. 7. Microphotographs of the thickness of the median membrane of the interlobular arteries of the kidneys in the studied groups: a – group 1; б – group 2; в – group 3 (staining with hematoxylin and eosin; magnification ×200)

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9. Fig. 8. Microphotographs of peritubular capillaries in the kidneys of the rabbits studied: a – group 1; б – group 2;в – group 3 (staining with hematoxylin and eosin; magnification ×400)

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