urmjУральский медицинский журналUral Medical Journal2949-4389Ural State Medical University10.52420/umj.24.2.56FRAAMDurmj-1777Research ArticleОригинальные статьи | Original articlesOriginal articlesВлияние моделирования аутофагии в стволовых клетках на регенерацию миелоидной ткани мышей после их сублетального облученияThe Effect of Autophagy Modeling in Stem Cells on the Regeneration of Myeloid Tissue in Mice after Their Sublethal Irradiationhttps://orcid.org/0000-0002-7475-9517ИвановВ. А.IvanovV. A.

Владислав Александрович Иванов — аспирант кафедры патологической физиологии, институт фундаментальной медицины, Уральский ГМУ; терапевт терапевтического отделения № 11, Свердловский областной клинический психоневрологический госпиталь для ветеранов войн.

Екатеринбург

Vladislav A. Ivanov — Postgraduate Student of the Department of Pathologic Physiology, Institute of Fundamental Medicine, Ural SMU; Therapist of the Therapeutic Department No. 11, Sverdlovsk Regional Clinical Neuropsychiatric Hospital for War Veterans.

Ekaterinburg

vlanov123@yandex.ruhttps://orcid.org/0000-0002-5698-8404ГребневД. Ю.GrebnevD. Yu.

Дмитрий Юрьевич Гребнев — доктор медицинских наук, доцент, заведующий кафедрой патологической физиологии, институт фундаментальной медицины, Уральский ГМУ; старший научный сотрудник лаборатории антивозрастных технологий, Институт медицинских клеточных технологий.

Екатеринбург

Dmitry Y. Grebnev — Doctor of Sciences (Medicine), Associate Professor, Head of the Department of Pathological Physiology, Institute of Fundamental Medicine, Ural SMU; Senior Researcher of the Laboratory of Anti‑Aging Technologies, Institute of Medical Cell Technologies.

Ekaterinburg

dr-grebnev77@mail.ruhttps://orcid.org/0000-0002-6895-7947МаклаковаИ. Ю.MaklakovaI. Yu.

Ирина Юрьевна Маклакова — доктор медицинских наук, доцент, заведующий кафедрой нормальной физиологии, институт фундаментальной медицины, Уральский ГМУ; старший научный сотрудник лаборатории антивозрастных технологий, Институт медицинских клеточных технологий.

Екатеринбург

Irina Y. Maklakova — Doctor of Sciences (Medicine), Associate Professor, Head of the Department of Normal Physiology, Institute of Fundamental Medicine, Ural SMU; Senior Researcher of the Laboratory of Anti‑Aging Technologies, Institute of Medical Cell Technologies.

Ekaterinburg

makliu@mail.ruhttps://orcid.org/0000-0003-0966-9571БазарныйВ. В.BazarnyiV. V.

Владимир Викторович Базарный — доктор медицинских наук, профессор, профессор кафедры патологической физиологии, главный научный сотрудник отдела общей патологии центральной научно‑исследовательской лаборатории, директор института фундаментальной медицины.

Екатеринбург

Vladimir V. Bazarnyi — Doctor of Sciences (Medicine), Professor, Professor of the Department of Pathological Physiology, Chief Researcher of the Department of General Pathology of the Central Research Laboratory, Director of the Institute of Fundamental Medicine, Ural SMU.

Ekaterinburg

vlad-bazarny@yandex.ruhttps://orcid.org/0000-0002-4921-7222ПолушинаЛ. Г.PolushinaL. G.

Лариса Георгиевна Полушина — кандидат медицинских наук, старший научный сотрудник отдела общей патологии центральной научно‑исследовательской лаборатории, институт фундаментальной медицины.

Екатеринбург

Larisa G. Polushina — Candidate of Sciences (Medicine), Senior Researcher of the Department of General Pathology of the Central Research Laboratory, Institute of Fundamental Medicine.

Ekaterinburg

polushina-larisa@bk.ruУральский государственный медицинский университет; Свердловский областной клинический психоневрологический госпиталь для ветеранов войнРоссияUral State Medical University; Sverdlovsk Regional Clinical Neuropsychiatric Hospital for War VeteransRussian FederationУральский государственный медицинский университет; Институт медицинских клеточных технологийРоссияUral State Medical University; Institute of Medical Cell TechnologiesRussian FederationУральский государственный медицинский университетРоссияUral State Medical UniversityRussian Federation20250505202524256–70Copyright © Иванов В.А., Гребнев Д.Ю., Маклакова И.Ю., Базарный В.В., Полушина Л.Г., 20252025Иванов В.А., Гребнев Д.Ю., Маклакова И.Ю., Базарный В.В., Полушина Л.Г.Ivanov V.A., Grebnev D.Y., Maklakova I.Y., Bazarnyi V.V., Polushina L.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.umjusmu.ru/jour/article/view/1777Введение

Введение. Острая лучевая болезнь в настоящее время остается одной из актуальных проблем современной медицины. Новая стратегия с использованием мезенхимальных стволовых клеток (МСК) показывает свою эффективность. Однако степень и результаты научной разработанности терапии МСК противоречивы и требуют дальнейшего исследования с оценкой пролиферативной и секреторной активности, в частности выработки гемопоэз-индуцирующих факторов роста, уровня активации гемопоэза.

Цель работы — моделирование процесса аутофагии с оценкой степени восстановления гемопоэза с использованием модулированных МСК.

Материалы и методы

Материалы и методы. Эксперимент проведен на 60 аутбредных мышах. Все группы животных, за исключением контрольной, подверглись воздействию ионизирующего излучения (ИИ) с последующими трансплантацией модулированных и немодулированных МСК, оценкой ретикулоцитов и лейкоцитарной формулы в анализе крови, а также костного мозга с подсчетом миелограммы и проведением иммуноферментного анализа. Статистический анализ проводился с использованием программы IBM SPSS Statistics 27.

Результаты

Результаты. После воздействия ИИ отмечается снижение лимфоидного (–45,0 %), нейтрофильного (–19,5 %) и мегакариоцитарного (–52,2 %) ростков. Экспрессия SCF и Flt3-ligand была выше в группе МСК ++ трегалоза по сравнению с рапамицином на 16,3 % и 19,7 % соответственно. Отмечен терапевтический эффект применения МСК в виде повышения клеточности костного мозга на +11,1 % за счет клеток нейтрофильного и лимфоидного дифферонов. Применение МСК с активированной в них mTOR-независимой аутофагией сопровождалось большим увеличением клеточности костного мозга среди исследуемых групп: лимфоциты +12,9 %, мегакариоциты +15,2 %. При ингибировании аутофагии в МСК отмечается снижение миелокариоцитов (–8,7 %), нейтрофильного (–14,5 %) и лимфоидного (–9,8 %) дифферонов.

Заключение

Заключение. Применения МСК с активированной mTOR-независимой аутофагией имеет больший терапевтический потенциал в восстановлении гемопоэза. Ингибирование аутофагии в МСК ухудшает их биологические свойства в отношении выработки факторов роста и регенерации миелоидной ткани после воздействия ИИ.

Introduction

Introduction. Acute radiation disease is one of the urgent problems of modern medicine. The new approach using mesenchymal stem cells (MSCs) show its effectiveness. Results of MSC therapy is contradictory and requires further researches to assess the production of hematopoiesis-inducing growth factors and the level of hematopoiesis activation.

The purpose of the study was modeling of autophagy process with estimation of the degree of hematopoiesis restoration using modulated MSCs.

Materials and methods

Materials and methods. The experiment was carried out on 60 outbred mice. Animals were exposed to ionizing radiation (IR) with transplantation of modulated and unmodulated MSCs to analyze reticulocyte, leukocyte formula, bone marrow with myelogram counting and enzyme immunoassay. Statistical analysis was performed using IBM SPSS Statistics 27 program.

Results and discussion

Results and discussion. After IR exposure, a decreased in lymphoid (–45.0 %), neutrophilic (–19.5 %) and megakaryocyte lineages (–52.2 %) was noted. Expression of SCF and Flt3-ligand was higher in the MSC + trehalose group compared to rapamycin by 16.3 % and 19.7 %. Using MSCs increased bone marrow cellularity by +11.1 % due to neutrophilic and lymphoid cells. MSC with activated mTOR-independent autophagy increased in bone marrow cellularity among the studied groups: lymphocytes +12.9 %, megakaryocytes +15.2 %. Inhibition of autophagy in MSC decreased numbers of myelokaryocytes (–8.7 %), neutrophilic (–14.5 %) and lymphoid (–9.8 %) cells.

Conclusion

Conclusion. The use of MSCs with activated mTOR-independent autophagy has a greater therapeutic potential in the restoration of hematopoiesis. Inhibition of autophagy in MSCs worsens their biological properties in terms of growth factor production and myeloid tissue regeneration after IR exposure.

аутофагиямезенхимальные стволовые клеткиионизирующее излучениегемопоэзmTORтрегалозапролиферацияautophagymesenchymal stem cellsionizing radiationhematopoiesismTORtrehaloseproliferationReferencesJones JA, Karouia F, Cristea O, Casey RC, Popov D, Maliev V. Ionizing radiation as a carcinogen. In: Comprehensive toxicology. 3rd ed. Elsevier Science; 2018. P. 183–225. DOI: https://doi.org/10.1016/B978-0-12801238-3.64295-2.Jones JA, Karouia F, Cristea O, Casey RC, Popov D, Maliev V. Ionizing radiation as a carcinogen. In: Comprehensive toxicology. 3rd ed. Elsevier Science; 2018. P. 183–225. DOI: https://doi.org/10.1016/B978-0-12801238-3.64295-2.Benderitter M, Caviggioli F, Chapel A, Coppes RP, Guha C, Klinger M, et al. Stem cell therapies for the treatment of radiation-induced normal tissue side effects. Antioxidants & Redox Signaling. 2014;21(2):338–355. DOI: https://doi.org/10.1089/ars.2013.5652.Benderitter M, Caviggioli F, Chapel A, Coppes RP, Guha C, Klinger M, et al. Stem cell therapies for the treatment of radiation-induced normal tissue side effects. Antioxidants & Redox Signaling. 2014;21(2):338–355. DOI: https://doi.org/10.1089/ars.2013.5652.Puckett Y, Al-Naser YA, Nappe TM. Ionizing radiation. In: StatPearls. Treasure Island: StatPearls Publishing. PMID: https://pubmed.gov/30480970.Puckett Y, Al-Naser YA, Nappe TM. Ionizing radiation. In: StatPearls. Treasure Island: StatPearls Publishing. PMID: https://pubmed.gov/30480970.Fukumoto R. Mesenchymal stem cell therapy for acute radiation syndrome. Military Medical Research. 2016;3:17. DOI: https://doi.org/10.1186/s40779-016-0086-1.Fukumoto R. Mesenchymal stem cell therapy for acute radiation syndrome. Military Medical Research. 2016;3:17. DOI: https://doi.org/10.1186/s40779-016-0086-1.Friedenstein J, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230–247. DOI: https://doi.org/10.1097/00007890-196803000-00009.Friedenstein J, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230–247. DOI: https://doi.org/10.1097/00007890-196803000-00009.Deans J, Moseley AB. Mesenchymal stem cells: Biology and potential clinical uses. Experimental Hematology. 2000;28(8):875–884. DOI: https://doi.org/10.1016/s0301-472x(00)00482-3.Deans J, Moseley AB. Mesenchymal stem cells: Biology and potential clinical uses. Experimental Hematology. 2000;28(8):875–884. DOI: https://doi.org/10.1016/s0301-472x(00)00482-3.El-Naseery NI, Elewa YHA, El-Behery EI, Dessouky AA. Human umbilical cord blood-derived mesenchymal stem cells restored hematopoiesis by improving radiation induced bone marrow niche remodeling in rats. Annals of Anatomy — Anatomischer Anzeiger. 2023;250:152131. DOI: https://doi.org/10.1016/j.aanat.2023.152131.El-Naseery NI, Elewa YHA, El-Behery EI, Dessouky AA. Human umbilical cord blood-derived mesenchymal stem cells restored hematopoiesis by improving radiation induced bone marrow niche remodeling in rats. Annals of Anatomy — Anatomischer Anzeiger. 2023;250:152131. DOI: https://doi.org/10.1016/j.aanat.2023.152131.Xie Q, Liu R, Jiang J, Peng J, Yang C, Zhang W, et al. What is the impact of human umbilical cord mesenchymal stem cell transplantation on clinical treatment? Stem Cell Research & Therapy. 2020;11(1):519. DOI: https://doi.org/10.1186/s13287-020-02011-z.Xie Q, Liu R, Jiang J, Peng J, Yang C, Zhang W, et al. What is the impact of human umbilical cord mesenchymal stem cell transplantation on clinical treatment? Stem Cell Research & Therapy. 2020;11(1):519. DOI: https://doi.org/10.1186/s13287-020-02011-z.Dehnavi S, Sadeghi M, Tavakol Afshari J, Mohammadi M. Interactions of mesenchymal stromal/stem cells and immune cells following MSC-based therapeutic approaches in rheumatoid arthritis. Cell Immunology. 2023;393–394:104771. DOI: https://doi.org/10.1016/j.cellimm.2023.104771.Dehnavi S, Sadeghi M, Tavakol Afshari J, Mohammadi M. Interactions of mesenchymal stromal/stem cells and immune cells following MSC-based therapeutic approaches in rheumatoid arthritis. Cell Immunology. 2023;393–394:104771. DOI: https://doi.org/10.1016/j.cellimm.2023.104771.Sarıkaya A, Aydın G, Özyüncü Ö, Şahin E, Uçkan-Çetinkaya D, Aerts-Kaya F. Comparison of immune modulatory properties of human multipotent mesenchymal stromal cells derived from bone marrow and placenta. Biotechnic & Histochemistry. 2022;97(2):79–89. DOI: https://doi.org/10.1080/10520295.2021.1885739.Sarıkaya A, Aydın G, Özyüncü Ö, Şahin E, Uçkan-Çetinkaya D, Aerts-Kaya F. Comparison of immune modulatory properties of human multipotent mesenchymal stromal cells derived from bone marrow and placenta. Biotechnic & Histochemistry. 2022;97(2):79–89. DOI: https://doi.org/10.1080/10520295.2021.1885739.Arki MK, Moeinabadi-Bidgoli K, Niknam B, Mohammadi P, Hassan M, Hossein-Khannazer N, et al. Immunomodulatory performance of GMP-compliant, clinical-grade mesenchymal stromal cells from four different sources. Heliyon. 2024;10(2):e24948. DOI: https://doi.org/10.1016/j.heliyon.2024.e24948.Arki MK, Moeinabadi-Bidgoli K, Niknam B, Mohammadi P, Hassan M, Hossein-Khannazer N, et al. Immunomodulatory performance of GMP-compliant, clinical-grade mesenchymal stromal cells from four different sources. Heliyon. 2024;10(2):e24948. DOI: https://doi.org/10.1016/j.heliyon.2024.e24948.Abumaree MH, Abomaray FM, Alshabibi MA, AlAskar AS, Kalionis B. Immunomodulatory properties of human placental mesenchymal stem/stromal cells. Placenta. 2017;59:87–95. DOI: https://doi.org/10.1016/j.placenta.2017.04.003.Abumaree MH, Abomaray FM, Alshabibi MA, AlAskar AS, Kalionis B. Immunomodulatory properties of human placental mesenchymal stem/stromal cells. Placenta. 2017;59:87–95. DOI: https://doi.org/10.1016/j.placenta.2017.04.003.Mathew SA, Naik C, Cahill PA, Bhonde RR. Placental mesenchymal stromal cells as an alternative tool for therapeutic angiogenesis. Cellular and Molecular Life Sciences. 2020;77(2):253–265. DOI: https://doi.org/10.1007/s00018-019-03268-1.Mathew SA, Naik C, Cahill PA, Bhonde RR. Placental mesenchymal stromal cells as an alternative tool for therapeutic angiogenesis. Cellular and Molecular Life Sciences. 2020;77(2):253–265. DOI: https://doi.org/10.1007/s00018-019-03268-1.Maklakova IYu, Yastrebov AP, Grebnev D Yu. Changing of the morphometric and cytological indexes of the spleen in the condition of acute blood loss on the background of stem cells insertion. Uspekhi gerontologii. 2015;28(2):218–221. (In Russ.). EDN: https://elibrary.ru/UDENCH.Maklakova IYu, Yastrebov AP, Grebnev D Yu. Changing of the morphometric and cytological indexes of the spleen in the condition of acute blood loss on the background of stem cells insertion. Uspekhi gerontologii. 2015;28(2):218–221. (In Russ.). EDN: https://elibrary.ru/UDENCH.Grebnev DYu, Maklakova IYu, Yastrebov AP. The effect of different doses of HSC during combined transplantation with MSC on the regeneration of myeloid tissue after exposure to ionizing radiation. Journal of Ural Medical Academic Science. 2014;(5):73–75. (In Russ.). EDN: https://www.elibrary.ru/TKZMWB.Grebnev DYu, Maklakova IYu, Yastrebov AP. The effect of different doses of HSC during combined transplantation with MSC on the regeneration of myeloid tissue after exposure to ionizing radiation. Journal of Ural Medical Academic Science. 2014;(5):73–75. (In Russ.). EDN: https://www.elibrary.ru/TKZMWB.Grebnev DYu, Yastrebov AP, Maklakova IYu. Changes in the morphometric parameters of the spleen of old laboratory animals after exposure to ionizing radiation on the background of stem cell transplantation. Kazan Medical Journal. 2013;94(6):911–914. (In Russ.). DOI: https://doi.org/10.17816/KMJ1818.Grebnev DYu, Yastrebov AP, Maklakova IYu. Changes in the morphometric parameters of the spleen of old laboratory animals after exposure to ionizing radiation on the background of stem cell transplantation. Kazan Medical Journal. 2013;94(6):911–914. (In Russ.). DOI: https://doi.org/10.17816/KMJ1818.Maklakova IYu, Grebnev DYu, Osipenko AV. Influence of combined transplantation of multipotent mesenchymal stromal cells and stellate liver cells on its morphofunctional state after partial hepatectomy. Ural Medical Journal. 2021;20(1):16–22. (In Russ.). DOI: https://doi.org/10.52420/2071-5943-2021-20-1-16-22.Maklakova IYu, Grebnev DYu, Osipenko AV. Influence of combined transplantation of multipotent mesenchymal stromal cells and stellate liver cells on its morphofunctional state after partial hepatectomy. Ural Medical Journal. 2021;20(1):16–22. (In Russ.). DOI: https://doi.org/10.52420/2071-5943-2021-20-1-16-22.Azarbarz N, Nejaddehbashi F, Khorsandi L, Bijan Nejad D, Sayyahi A. Autophagy enhances the differentiation of insulin-producing cells from Wharton’s jelly-derived mesenchymal stem cells. Tissue and Cell. 2024;88:102384. DOI: https://doi.org/10.1016/j.tice.2024.102384.Azarbarz N, Nejaddehbashi F, Khorsandi L, Bijan Nejad D, Sayyahi A. Autophagy enhances the differentiation of insulin-producing cells from Wharton’s jelly-derived mesenchymal stem cells. Tissue and Cell. 2024;88:102384. DOI: https://doi.org/10.1016/j.tice.2024.102384.Verma J, Rai AK, Satija NK. Autophagy perturbation upon acute pyrethroid treatment impacts adipogenic commitment of mesenchymal stem cells. Pesticide Biochemistry and Physiology. 2023;195:105566. DOI: https://doi.org/10.1016/j.pestbp.2023.105566.Verma J, Rai AK, Satija NK. Autophagy perturbation upon acute pyrethroid treatment impacts adipogenic commitment of mesenchymal stem cells. Pesticide Biochemistry and Physiology. 2023;195:105566. DOI: https://doi.org/10.1016/j.pestbp.2023.105566.Liu S, Yao S, Yang H, Liu S, Wang Y. Autophagy: Regulator of cell death. Cell Death & Disease. 2023; 14(10):648. DOI: https://doi.org/10.1038/s41419-023-06154-8.Liu S, Yao S, Yang H, Liu S, Wang Y. Autophagy: Regulator of cell death. Cell Death & Disease. 2023; 14(10):648. DOI: https://doi.org/10.1038/s41419-023-06154-8.Klionsky DJ, Petroni G, Amaravadi RK, Baehrecke EH, Ballabio A, Boya P, et al. Autophagy in major human diseases. The EMBO Journal. 2021;40(19):e108863. DOI: https://doi.org/10.15252/embj.2021108863.Klionsky DJ, Petroni G, Amaravadi RK, Baehrecke EH, Ballabio A, Boya P, et al. Autophagy in major human diseases. The EMBO Journal. 2021;40(19):e108863. DOI: https://doi.org/10.15252/embj.2021108863.Molaei S, Roudkenar MH, Amiri F, Harati MD, Bahadori M, Jaleh F, et al. Down-regulation of the autophagy gene, ATG7, protects bone marrow-derived mesenchymal stem cells from stressful conditions. Blood Research. 2015;50(2):80–86. DOI: https://doi.org/10.5045/br.2015.50.2.80.Molaei S, Roudkenar MH, Amiri F, Harati MD, Bahadori M, Jaleh F, et al. Down-regulation of the autophagy gene, ATG7, protects bone marrow-derived mesenchymal stem cells from stressful conditions. Blood Research. 2015;50(2):80–86. DOI: https://doi.org/10.5045/br.2015.50.2.80.Gao L, Cen S, Wang P, Xie Z, Liu Z, Deng W, et al. Autophagy improves the immunosuppression of CD4+ T cells by mesenchymal stem cells through transforming growth factor-β1. Stem Cells Translational Medicine. 2016;5(11):1496–1505. DOI: https://doi.org/10.5966/sctm.2015–0420.Gao L, Cen S, Wang P, Xie Z, Liu Z, Deng W, et al. Autophagy improves the immunosuppression of CD4+ T cells by mesenchymal stem cells through transforming growth factor-β1. Stem Cells Translational Medicine. 2016;5(11):1496–1505. DOI: https://doi.org/10.5966/sctm.2015–0420.Kim KW, Moon SJ, Park MJ, Kim BM, Kim EK, Lee SH, et al. Optimization of adipose tissue-derived mesenchymal stem cells by rapamycin in a murine model of acute graft-versus-host disease. Stem Cell Research & Therapy. 2015;6:202. DOI: https://doi.org/10.1186/s13287-015-0197–8. Erratum in: Stem Cell Research & Therapy. 2016;7(1):80. DOI: https://doi.org/10.1186/s13287-016-0336-x.Kim KW, Moon SJ, Park MJ, Kim BM, Kim EK, Lee SH, et al. Optimization of adipose tissue-derived mesenchymal stem cells by rapamycin in a murine model of acute graft-versus-host disease. Stem Cell Research & Therapy. 2015;6:202. DOI: https://doi.org/10.1186/s13287-015-0197–8. Erratum in: Stem Cell Research & Therapy. 2016;7(1):80. DOI: https://doi.org/10.1186/s13287-016-0336-x.Dang S, Yu ZM, Zhang CY, Zheng J, Li KL, Wu Y, et al. Autophagy promotes apoptosis of mesenchymal stem cells under inflammatory microenvironment. Stem Cell Research & Therapy. 2015;6:247. DOI: https://doi.org/10.1186/s13287-015-0245-4.Dang S, Yu ZM, Zhang CY, Zheng J, Li KL, Wu Y, et al. Autophagy promotes apoptosis of mesenchymal stem cells under inflammatory microenvironment. Stem Cell Research & Therapy. 2015;6:247. DOI: https://doi.org/10.1186/s13287-015-0245-4.Chen X, Li M, Li L, Xu S, Huang D, Ju M, et al. Trehalose, sucrose and raffinose are novel activators of autophagy in human keratinocytes through an mTOR-independent pathway. Scientific Reports. 2016;6:28423. DOI: https://doi.org/10.1038/srep28423.Chen X, Li M, Li L, Xu S, Huang D, Ju M, et al. Trehalose, sucrose and raffinose are novel activators of autophagy in human keratinocytes through an mTOR-independent pathway. Scientific Reports. 2016;6:28423. DOI: https://doi.org/10.1038/srep28423.Kim JS, Jang WS, Lee S, Son Y, Park S, Lee SS. A study of the effect of sequential injection of 5-androstenediol on irradiation-induced myelosuppression in mice. Archives of Pharmacal Research. 2015;38(6):1213–1222. DOI: https://doi.org/10.1007/s12272-014-0483-5.Kim JS, Jang WS, Lee S, Son Y, Park S, Lee SS. A study of the effect of sequential injection of 5-androstenediol on irradiation-induced myelosuppression in mice. Archives of Pharmacal Research. 2015;38(6):1213–1222. DOI: https://doi.org/10.1007/s12272-014-0483-5.Parasuraman S, Raveendran R, Kesavan R. Blood sample collection in small laboratory animals. Journal of Pharmacology & Pharmacotherapeutics. 2010;1(2):87–93. DOI: https://doi.org/10.4103/0976-500X.72350.Parasuraman S, Raveendran R, Kesavan R. Blood sample collection in small laboratory animals. Journal of Pharmacology & Pharmacotherapeutics. 2010;1(2):87–93. DOI: https://doi.org/10.4103/0976-500X.72350.Yu H, Zhang T, Lu H, Ma Q, Zhao D, Sun J, et al. Granulocyte colony-stimulating factor (G-CSF) mediates bone resorption in periodontitis. BMC Oral Health. 2021;21(1):299. DOI: https://doi.org/10.1186/s12903021-01658-1.Yu H, Zhang T, Lu H, Ma Q, Zhao D, Sun J, et al. Granulocyte colony-stimulating factor (G-CSF) mediates bone resorption in periodontitis. BMC Oral Health. 2021;21(1):299. DOI: https://doi.org/10.1186/s12903021-01658-1.Durandt C, van Vollenstee FA, Dessels C, Kallmeyer K, de Villiers D, Murdoch C, et al. Novel flow cytometric approach for the detection of adipocyte subpopulations during adipogenesis. Journal of Lipid Research. 2016;57(4):729–742. DOI: https://doi.org/10.1194/jlr.D065664.Durandt C, van Vollenstee FA, Dessels C, Kallmeyer K, de Villiers D, Murdoch C, et al. Novel flow cytometric approach for the detection of adipocyte subpopulations during adipogenesis. Journal of Lipid Research. 2016;57(4):729–742. DOI: https://doi.org/10.1194/jlr.D065664.Chinnadurai R, Forsberg MH, Kink JA, Hematti P, Capitini CM. Use of MSCs and MSC-educated macrophages to mitigate hematopoietic acute radiation syndrome. Current Stem Cell Reports. 2020;6(3):77–85. DOI: https://doi.org/10.1007/s40778-020-00176-0.Chinnadurai R, Forsberg MH, Kink JA, Hematti P, Capitini CM. Use of MSCs and MSC-educated macrophages to mitigate hematopoietic acute radiation syndrome. Current Stem Cell Reports. 2020;6(3):77–85. DOI: https://doi.org/10.1007/s40778-020-00176-0.Schroeder T. Hematopoietic stem cell heterogeneity: subtypes, not unpredictable behavior. Cell Stem Cell. 2010;6(3):203–207. DOI: https://doi.org/10.1016/j.stem.2010.02.006.Schroeder T. Hematopoietic stem cell heterogeneity: subtypes, not unpredictable behavior. Cell Stem Cell. 2010;6(3):203–207. DOI: https://doi.org/10.1016/j.stem.2010.02.006.Du J, He H, Li Z, He J, Bai Z, Liu B, et al. Integrative transcriptomic analysis of developing hematopoietic stem cells in human and mouse at single-cell resolution. Biochemical and Biophysical Research Communications. 2021;558:161–167. DOI: https://doi.org/10.1016/j.bbrc.2021.04.058.Du J, He H, Li Z, He J, Bai Z, Liu B, et al. Integrative transcriptomic analysis of developing hematopoietic stem cells in human and mouse at single-cell resolution. Biochemical and Biophysical Research Communications. 2021;558:161–167. DOI: https://doi.org/10.1016/j.bbrc.2021.04.058.Wilson NK, Kent DG, Buettner F, Shehata M, Macaulay IC, Calero-Nieto FJ, et al. Combined single-cell functional and gene expression analysis resolves heterogeneity within stem cell populations. Cell Stem Cell. 2015;16(6):712–724. DOI: https://doi.org/10.1016/j.stem.2015.04.004.Wilson NK, Kent DG, Buettner F, Shehata M, Macaulay IC, Calero-Nieto FJ, et al. Combined single-cell functional and gene expression analysis resolves heterogeneity within stem cell populations. Cell Stem Cell. 2015;16(6):712–724. DOI: https://doi.org/10.1016/j.stem.2015.04.004.Kostjunina VS, Petyovka NV, Potapnev MP. Different expression of hematopoietic-supporting genes in cord, placental and bone marrow mesenchymal stromal cells. Genes & Cells. 2015;10(1):61–68. (In Russ.). DOI: https://doi.org/10.23868/gc120484.Kostjunina VS, Petyovka NV, Potapnev MP. Different expression of hematopoietic-supporting genes in cord, placental and bone marrow mesenchymal stromal cells. Genes & Cells. 2015;10(1):61–68. (In Russ.). DOI: https://doi.org/10.23868/gc120484.Lamark T, Johansen T. Aggrephagy: Selective disposal of protein aggregates by macroautophagy. International Journal of Cell Biology. 2012;2012:736905. DOI: https://doi.org/10.1155/2012/736905.Lamark T, Johansen T. Aggrephagy: Selective disposal of protein aggregates by macroautophagy. International Journal of Cell Biology. 2012;2012:736905. DOI: https://doi.org/10.1155/2012/736905.de la Cruz López KG, Toledo Guzmán ME, Sánchez EO, García Carrancá A. mTORC1 as a regulator of mitochondrial functions and a therapeutic target in cancer. Frontiers in Oncology. 2019;9:1373. DOI: https://doi.org/10.3389/fonc.2019.01373.de la Cruz López KG, Toledo Guzmán ME, Sánchez EO, García Carrancá A. mTORC1 as a regulator of mitochondrial functions and a therapeutic target in cancer. Frontiers in Oncology. 2019;9:1373. DOI: https://doi.org/10.3389/fonc.2019.01373.

The authors declare that there are no conflicts of interest present.