Болдырева Мария Александровна
Факультет биологии и биотехнологии
Профессиональные интересы
Должности
- Доцент — Факультет биологии и биотехнологии, Базовая кафедра Института биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова РАН
Био
- · Начала работать в НИУ ВШЭ в 2020 году.
Образование
- 1996 · Кандидат биологических наук
- 1992 · Специалитет: Московский государственный университет им. М.В. Ломоносова, специальность «Физиология», квалификация «Биолог»
Опыт работы
- · 2008-2011: гг
- · 2005-2008: гг
- · ФГБУ Национальный медицинский исследовательский центр кардиологии Минздрава РФ, ул. Академика Чазова, 15а, 121552 Москва, Лаборатория Ангиогенеза, старший научный сотрудник
- · Чтение курсов лекций для студентов факультета Фундаментальной медицины и факультета Психологии МГУ им. М.В.Ломоносова
- · Московский государственный медико-стоматологический университет им. А.И.Евдокимова (МГМСУ), каф. Нормальной физиологии, Преподаватель
- · Президиум Российской Академии Наук, Секция Физиологии Отделения Биологических наук, Главный специалист аппарата.
Награды и поощрения
- · Надбавка за публикацию в журнале из Списка А (и приравненном к нему научном издании) (2024–2025, 2023–2024)
- · Лучший преподаватель — 2025
Конференции (2)
Показать все
- · 2019: The 27th ESGCT Annual Congress (Barselona). Доклад: Adipose stromal cell sheet producing hepatocyte growth factor (HGF) effectively stimulates recovery of ischemic skeletal muscle in mouse hind limb ischemia model
- · 2018: ASGCT 21st Annual Meeting (Chicago). Доклад: SPK-9001: Adeno-Associated Virus Mediated Gene Transfer for Hemophilia B - Sustained Fix Activity, Persistent Endogenous Prophylaxis and Improved Quality of Life at One Year and Beyond
Идентификаторы исследователя
- ORCID:
0000-0002-8309-0018 - ResearcherID:
J-9417-2015 - SPIN РИНЦ:
2132-3690 - Google Scholar: https://scholar.google.com/citations?hl=ru&user=MdBtzRkAAAAJ&view_op=list_works&gmla=AJsN-F4wfM0mFaJGPHJrwZUJXQJRtLfGp0yh34FGnpWvlCmWlL-mhk9TCatyCsbgjsMJOjCV7YEX3Mx7YlNk72mrZcPC5a7N1DxumXsvz0m2Pi0lspLTIo8
- Scopus AuthorID:
6701309208
Публикации (16)
uPAR deficiency triggers TGFβ1-mediated fibrotic remodeling in a cardiac perivascular-like microenvironment
2026 · ARTICLE · en
Background Cardiac fibrosis represents a significant health burden, with endothelial dysfunction and damaged perivascular microenvironment increasingly recognized as key contributors to fibrotic remodeling. The urokinase plasminogen activator receptor (uPAR), a critical component of the urokinase system, plays a pivotal role in vascular remodeling and fibrosis. While prior evidence indicates that uPAR deficiency leads to microvascular dysfunction and perivascular fibrosis, the underlying mechanisms remain poorly defined. This study investigates how uPAR deficiency contributes to fibrotic remodeling of the cardiac perivascular-like microenvironment. Methods Single-cell RNA sequencing data analysis and immunofluorescence staining on mouse heart cryosections were performed to characterize uPAR expression within the cardiac perivascular microenvironment. To model this microenvironment in vitro, cardiospheres (CSs) were generated from non-myocyte cardiac cells of wild-type and uPAR-knockout mice. CRISPR/Cas9-generated Plaur knockout (KO) 3T3 fibroblasts (FBs) were employed as model stromal cells. Pro-fibrotic activation of FBs was induced by TGFβ1 treatment. Comparative analyses of extracellular matrix (ECM) deposition, fibrotic cell transformation, and comprehensive secretome profiling was conducted using western blotting. Results Our findings demonstrated that uPAR was expressed by endothelial cells (ECs) and FBs within the cardiac perivascular microenvironment. uPAR deficiency exacerbated profibrotic stimuli in CSs, including elevated active TGFβ1, impaired integrin functions, and altered cell secretome. These alterations collectively disrupt critical cell-cell and cell-matrix interactions, leading to increased ECM deposition, EC loss and decreased cell viability. Using Plaur KO FBs, we demonstrated that uPAR deficiency amplified TGFβ1-mediated Akt signaling pathway and ECM deposition. Conclusions Our study reveals that uPAR loss drives fibrotic remodeling of the cardiac perivascular-like microenvironment and exacerbates TGFβ1-mediated effects, highlighting its potential as a therapeutic target for cardiac fibrosis.
Cardiac Regenerative Potential of Spiny Mice (Acomys cahirinus) Manifests Itself in Expansion of Pacemaker Myocardium and Predominance of Noncanonical, IK, ACH-Independent Pathway of Cholinergic Regulation in Cardiac Pacemaking
2025 · ARTICLE · en
Spiny mice (Acomys cahirinus) exhibit the ability to regenerate the damaged myocardium and functionalindices of the heart. demonstrated in various models of cardiac pathologies. Cardioregenerative potentialof Acomys is associated with partial preservation of the neonatal phenotype of cardiac tissue in adult animals.The electrophysiology and mechanisms regulating the heart rhythm in Acomys are extremely poorlyunderstood. The EEG was recorded in vivo and bioelectrical activity of the supraventricular myocardium wasevaluated and mapped in spiny mice. Pacemaker-type action potentials were detected in a significant part ofthe right atrium, and primary activation involved approximately 41% of the atrium surface in Acomys. Cholinergicstimulation caused pronounced suppression of automaticity and changed the activation pattern of thepacemaker myocardium. IKAch-independent mechanisms mediated the cholinergic inhibition of automaticityin Acomys. Thus, the cardioregenerative potential of spiny mice manifests itself in delocalization andnonclassical regulation of the cardiac pacemaker.
Thermogenesis and reduced lipid synthesis: one-anastomosis gastric bypass bariatric surgery 6-mo follow-ups in adipose tissue health context for type 2 diabetes
2025 · ARTICLE · en
Background: One-anastomosis gastric bypass (OAGB) represents a novel less invasive bariatric surgery technique which can significantly improve systemic metabolism and adipose tissue health in type 2 diabetes mellitus (T2DM) patients. Previously, we demonstrated that T2DM impairs proliferation and differentiation of adipose tissue progenitors. Methods: Obese patients with T2DM (N=10) underwent clinical examination and subcutaneous fat biopsy during bariatric surgery and in 6-months. Adipose-derived stem cells (ADSC) were isolated by enzymatic method. Cell proliferation was analyzed using MTT assay and immunocytochemistry. Adipogenesis and thermogenesis were assessed by confocal microscopy. Adipocytes metabolism was estimated by radioisotope tracing. Western blotting was employed to quantify protein expression. Results: Median weight loss after OAGB was 40 kg. OAGB resolved hyperinsulinemia and stimulated insulin sensitivity with changes in HOMA-IR and M-index up to 2-fold. Bariatric surgery significantly influenced properties of ADSC adipocytes: there were an increase in ADSC proliferation, decrease in white adipogenesis, activation of white and beige adipocytes lipid droplet fragmentation, activation of thermogenesis and inhibition of lipogenesis. Conclusions: OAGB promotes weight loss and insulin sensitivity and changes regenerative potential of ADSC. Enhanced ability of ADSC to proliferate and differentiate into thermogenic adipocytes with reduced activity of lipogenesis may prevent weight gain after bariatric surgery.
Osteogenic shift in the adipose-derived stem cells of Acomys cahirinus is linked to impaired adipose tissue self-renewal
2025 · ARTICLE · en
Over the past two decades, interest in spiny mice (Acomys species) has increased significantly, as they represent a unique model for experimental work (Gaire et al., 2021; Sandoval et al., 2020). In the process of evolution, Acomys sp. have retained an amazing ability to regeneration of various body tissues in adulthood. A number of studies have demonstrated the ability of Acomys sp. for complete regeneration and regrowth of tissues such as full-thickness skin (Seifert et al., 2021; Jiang et al., 2019; Brant et al., 2016), ear tissues (Santos et al., 2016; Gavrilyuk et al., 2016), skeletal muscles (Maden et al., 2018). Acomys sp. can even completely recover after a complete severing of the spinal cord (Nogueira-Rodriguez et al., 2022; Streeter et al., 2019). The regenerating tissue formed at the site of injury has no scars, which ensures a unique structural integrity. According to some physiological and behavioral characteristics, spiny mice are more similar to humans than to rodents, which explains the increased interest in using them in experimental work on the study of early development, brain behavior (Fricker & Kelly, 2024), hormonal background and the study of reproduction. Thus, the spiny mouse (Acomys cahirinus) is the only known rodent with human-like menstruation (Bellofiore et al., 2021; McKenna et al., 2022) and can synthesize cortisol as the major circulating glucocorticoid (Quinn et al., 2013) Moreover, Acomys sp. are of great interest as a model for dietary experiments, studying metabolic processes, feeding behavior, and the development of obesity in conjunction with diabetes. It was found that spiny mice exhibit a reduced capacity for insulin secretion, despite the presence of pancreatic islet hypertrophy and hyperplasia, before the onset of overt diabetes. In laboratory conditions with ad libitum feeding, Acomys sp. rapidly gained weight, developed obesity, diabetes with ketosis, and glucose intolerance, but without a gradual onset of pronounced insulin resistance and hyperinsulinemia, which may be related to their natural desert lifestyle (Shafrir E. et al., 2000; 2006). The developed diabetes was associated with the destruction of pancreatic β-cells due to their hypertrophy, but not related to excessive insulin secretory load. In dietary experiments conducted with Acomys sp., it was shown that a sucrose-rich diet did not lead to the onset of overt diabetes and ketosis, but resulted in an increase in T3 levels, which was presumably attributed to energy loss and thermogenic processes. The use of a high-fat diet revealed hypertrophy of pancreatic islets, as well as increased insulin content within them (Shafrir E., 2000). A significant part of the studies of adipose tissue were carried out using mouse models. However, more and more evidence suggests that there are species-specific differences, and the characteristics of adipose tissue in rodents differ significantly from those in humans. This does not always allow for a direct projection of experimental results and often leads to contradictory findings (Börgeson et al., 2022). Considering this fact, the use of Acomys as an experimental model may prove to be very promising for studying the properties of adipose tissue.
TGFβ1 Regulates Cellular Composition of In Vitro Cardiac Perivascular Niche Based on Cardiospheres
2024 · ARTICLE · en
The cardiac perivascular niche is a cellular microenvironment of a blood vessel. The principles of niche regulation are still poorly understood. We studied the effect of TGFβ1 on cells forming the cardiac perivascular niche using 3D cell culture (cardiospheres). Cardiospheres contained progenitor (c-Kit), endothelial (CD31), and mural (αSMA) cells, basement membrane proteins (laminin) and extracellular matrix proteins (collagen I, fibronectin). TGFβ1 treatment decreased the length of CD31+ microvasculature, VE cadherin protein level, and proportion of NG2+ cells, and increased proportion of αSMA+ cells and transgelin/SM22α protein level. We supposed that this effect is related to the stabilizing function of TGFβ1 on vascular cells: decreased endothelial cell proliferation, as shown for HUVEC, and activation of mural cell differentiation.
Transplantation of Adipose-Tissue-Engineered Constructs with CRISPR-Mediated UCP1 Activation
2023 · ARTICLE · en
Thermogenic adipocytes have potential utility for the development of approaches to treat type 2 diabetes and obesity-associated diseases. Although several reports have proved the positive effect of beige and brown adipocyte transplantation in obese mice, translation to human cell therapy needs improvement. Here, we describe the application of CRISPR activation (CRISPRa) technology for generating safe and efficient adipose-tissue-engineered constructs with enhanced mitochondrial uncoupling protein 1 (UCP1) expression. We designed the CRISPRa system for the activation of UCP1 gene expression. CRISPRa-UCP1 was delivered into mature adipocytes by a baculovirus vector. Modified adipocytes were transplanted in C57BL/6 mice, followed by analysis of grafts, inflammation and systemic glucose metabolism. Staining of grafts on day 8 after transplantation shows them to contain UCP1-positive adipocytes. Following transplantation, adipocytes remain in grafts and exhibit expression of PGC1α transcription factor and hormone sensitive lipase (HSL). Transplantation of CRISPRa-UCP1-modified adipocytes does not influence glucose metabolism or inflammation in recipient mice. We show the utility and safety of baculovirus vectors for CRISPRa-based thermogenic gene activation. Our findings suggest a means of improving existing cell therapy approaches using baculovirus vectors and CRISPRa for modification and transplantation of non-immunogenic adipocytes.
The Efficacy of HGF/VEGF Gene Therapy for Limb Ischemia in Mice with Impaired Glucose Tolerance: Shift from Angiogenesis to Axonal Growth and Oxidative Potential in Skeletal Muscle
2022 · ARTICLE · en
Background: Combined non-viral gene therapy (GT) of ischemia and cardiovascular disease is a promising tool for potential clinical translation. In previous studies our group has developed combined gene therapy by vascular endothelial growth factor 165 (VEGF165) + hepatocyte growth factor (HGF). Our recent works have demonstrated that a bicistronic pDNA that carries both human HGF and VEGF165 coding sequences has a potential for clinical application in peripheral artery disease (PAD). The present study aimed to test HGF/VEGF combined plasmid efficacy in ischemic skeletal muscle comorbid with predominant complications of PAD-impaired glucose tolerance and type 2 diabetes mellitus (T2DM). Methods: Male C57BL mice were housed on low-fat (LFD) or high-fat diet (HFD) for 10 weeks and metabolic parameters including FBG level, ITT, and GTT were evaluated. Hindlimb ischemia induction and plasmid administration were performed at 10 weeks with 3 weeks for post-surgical follow-up. Limb blood flow was assessed by laser Doppler scanning at 7, 14, and 21 days after ischemia induction. The necrotic area of m.tibialis anterior, macrophage infiltration, angio- and neuritogenesis were evaluated in tissue sections. The mitochondrial status of skeletal muscle (total mitochondria content, ETC proteins content) was assessed by Western blotting of muscle lysates. Results: At 10 weeks, the HFD group demonstrated impaired glucose tolerance in comparison with the LFD group. HGF/VEGF plasmid injection aggravated glucose intolerance in HFD conditions. Blood flow recovery was not changed by HGF/VEGF plasmid injection either in LFD or HFD conditions. GT in LFD, but not in HFD conditions, enlarged the necrotic area and CD68+ cells infiltration. However, HGF/VEGF plasmid enhanced neuritogenesis and enlarged NF200+ area on muscle sections. In HFD conditions, HGF/VEGF plasmid injection significantly increased mitochondria content and ETC proteins content. Conclusions: The current study demonstrated a significant role of dietary conditions in pre-clinical testing of non-viral GT drugs. HGF/VEGF combined plasmid demonstrated a novel aspect of potential participation in ischemic skeletal muscle regeneration, through regulation of innervation and bioenergetics of muscle. The obtained results made HGF/VEGF combined plasmid a very promising tool for PAD therapy in impaired glucose tolerance conditions.
Grain-based dietary background impairs restoration of blood flow and skeletal muscle during hindlimb ischemia in comparison with low-fat and high-fat diets
2022 · ARTICLE · en
Background: Among vascular pathologies associated with obesity peripheral artery disease (PAD) occupies the important position. In clinical practice nutritional interventions are recommended for PAD patients. In this study we investigate how the different dietary backgrounds affect the regeneration rate of ischemic hindlimb in mice. Methods: Male C57BL/6J mice were housed on three types of diet: low-fat (LFD), high-fat (HFD) and grain-based diet (GBD) during 13 weeks. Metabolic parameters including FBG level, ITT and GTT were evaluated. The blood flow was assessed by laser Doppler scanning on 7, 14 and 21 days after hindlimb ischemia. Necrotic area of m.tibialis, macrophage infiltration, angiogenesis/arteriogenesis were evaluated by histology. Glucose uptake in recovered skeletal muscle was analyzed using [3H]-2-deoxyglucose; GLUT1 and GLUT4 expression were assessed by Western blotting. Results: In our work we developed three experimental groups with different metabolic parameters: LFD with normal glucose metabolism, GBD with mild hyperglycemia and HFD with impaired glucose tolerance. GBD-fed mice had a tendency to increased necrosis of m.tibialis and significantly higher macrophage infiltration than LFD and HFD groups. Moreover, GBD-fed mice had a trend to decreased blood flow recovery and significantly impaired arteriogenesis. Recovered skeletal muscle of GBD-fed mice had lower glucose uptake and decreased level of GLUT4 expression. Conclusion: Thus, we conclude that dietary background and metabolic status determine the rate of post-ischemic regeneration including angiogenesis, skeletal muscle recovery and metabolic activity. The most effective regeneration is supported by LFD, while the lowest rate of regeneration occurs on GBD.
Features of the Population of Mouse Peritoneal Macrophages Isolated after Stimulation with Concanavalin A and Thioglycolate
2021 · ARTICLE · en
Murine peritoneal macrophages isolated from the lavage fluid after administration of thioglycolate and concanavalin A are presented by two populations of cells of different diameters. Polarization of macrophages into a proinflammatory (M1) phenotype is accompanied by an increase in number of small cells. Macrophages obtained after administration of thioglycolate demonstrate higher tendency to anti-inflammatory (M2) phenotype, while macrophages isolated after administration of concanavalin A are committed in the proinflammatory direction. Lactate level is increased in M1 macrophages in comparison with M2 cells, which indicates predominance of glycolytic metabolism. Macrophages obtained after administration of concanavalin A have reduced mitochondrial potential, which reflects a tendency to apoptosis. Autophagy activation and inhibition neutralize the differences in pro- and anti-inflammatory properties of polarized macrophages obtained after thioglycolate administration, but have less pronounced effect on macrophages obtained after administration concanavalin A. Autophagy inhibitor increases mitochondrial potential in non-polarized macrophages obtained after administration of concanavalin A. These results demonstrate divergent properties of macrophages obtained after administration of glycolate and concanavalin A due to the difference in the mechanisms of experimental peritonitis.
Therapeutic Angiogenesis by a “Dynamic Duo”: Simultaneous Expression of HGF and VEGF165 by Novel Bicistronic Plasmid Restores Blood Flow in Ischemic Skeletal Muscle
2020 · ARTICLE · en
Therapeutic angiogenesis is a promising strategy for relief of ischemic conditions, and gene delivery was used to stimulate blood vessels’ formation and growth. We have previously shown that intramuscular injection of a mixture containing plasmids encoding vascular endothelial growth factor (VEGF)165 and hepatocyte growth factor (HGF) leads to restoration of blood flow in mouse ischemic limb, and ecacy of combined delivery was superior to each plasmid administered alone. In this work, we evaluated di erent approaches for co-expression of HGF and VEGF165 genes in a panel of candidate plasmid DNAs (pDNAs) with internal ribosome entry sites (IRESs), a bidirectional promoter or two independent promoters for each gene of interest. Studies in HEK293T culture showed that all plasmids provided synthesis of HGF and VEGF165 proteins and stimulated capillary formation by human umbilical vein endothelial cells (HUVEC), indicating the biological potency of expressed factors. Tests in skeletal muscle explants showed a dramatic di erence and most plasmids failed to express HGF and VEGF165 in a significant quantity. However, a bicistronic plasmid with two independent promoters (cytomegalovirus (CMV) for HGF and chicken b-actin (CAG) for VEGF165) provided expression of both grow factors in skeletal muscle at an equimolar ratio. Ecacy tests of bicistronic plasmid were performed in a mouse model of hind limb ischemia. Intramuscular administration of plasmid induced significant restoration of perfusion compared to an empty vector and saline. These findings were supported by increased CD31+ capillary density in animals that received pHGF/VEGF. Overall, our study reports a first-in-class candidate gene therapy drug to deliver two pivotal angiogenic growth factors (HGF and VEGF165) with properties that provide basis for future development of treatment for an unmet medical need—peripheral artery disease and associated limb ischemia.
Курсы (2)
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Нейрогуморальная регуляция · 3 раза
2025/2026, 2024/2025, 2023/2024 · Бакалавриат · рус
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Физиология человека с основами биофизики · 5 раза
2025/2026, 2024/2025, 2023/2024, 2022/2023, 2021/2022 · Бакалавриат · рус