DSA Faculty
API
← к списку преподавателей

Болдырева Мария Александровна

Факультет биологии и биотехнологии

Профиль на hse.ru ↗ тел.: +7(495) 772-9590 | 15093
Публикаций
16
Языков
2
Наград
2
Конференций
2
Профиль Публикации (16) Курсы (2)

Профессиональные интересы

физиологиягенная и клеточная терапия

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

Публикации (16)

Cell Sheet Comprised of Mesenchymal Stromal Cells Overexpressing Stem Cell Factor Promotes Epicardium Activation and Heart Function Improvement in a Rat Model of Myocardium Infarction

2020 · ARTICLE · en

Cell therapy of the post-infarcted myocardium is still far from clinical use. Poor survival of transplanted cells, insufficient regeneration, and replacement of the damaged tissue limit the potential of currently available cell-based techniques. In this study, we generated a multilayered construct from adipose-derived mesenchymal stromal cells (MSCs) modified to secrete stem cell factor, SCF. In a rat model of myocardium infarction, we show that transplantation of SCF producing cell sheet induced activation of the epicardium and promoted the accumulation of c-kit positive cells in ischemic muscle. Morphometry showed the reduction of infarct size (16%) and a left ventricle expansion index (0.12) in the treatment group compared to controls (24-28%; 0.17-0.32). The ratio of viable myocardium was more than 1.5-fold higher, reaching 49% compared to the control (28%) or unmodified cell sheet group (30%). Finally, by day 30 after myocardium infarction, SCF-producing cell sheet transplantation increased left ventricle ejection fraction from 37% in the control sham-operated group to 53%. Our results suggest that, combining the genetic modification of MSCs and their assembly into a multilayered construct, we can provide prolonged pleiotropic effects to the damaged heart, induce endogenous regenerative processes, and improve cardiac function.

DOI ↗ PDF ↗

Transplantation of Adipose Stromal Cell Sheet Producing Hepatocyte Growth Factor Induces Pleiotropic Effect in Ischemic Skeletal Muscle

2019 · ARTICLE · en

Cell therapy remains a promising approach for the treatment of cardiovascular diseases. In this regard, the contemporary trend is the development of methods to overcome low cell viability and enhance their regenerative potential. In the present study, we evaluated the therapeutic potential of gene-modified adipose-derived stromal cells (ADSC) that overexpress hepatocyte growth factor (HGF) in a mice hind limb ischemia model. Angiogenic and neuroprotective e ects were assessed following ADSC transplantation in suspension or in the form of cell sheet. We found superior blood flow restoration, tissue vascularization and innervation, and fibrosis reduction after transplantation of HGF-producing ADSC sheet compared to other groups. We suggest that the observed e ects are determined by pleiotropic e ects of HGF, along with the multifactorial paracrine action of ADSC which remain viable and functionally active within the engineered cell construct. Thus, we demonstrated the high therapeutic potential of the utilized approach for skeletal muscle recovery after ischemic damage associated with complex tissue degenerative e ects.

DOI ↗ PDF ↗

Angiogenic and pleiotropic effects of VEGF165 and HGF combined gene therapy in a rat model of myocardial infarction.

2018 · ARTICLE · en

Since development of plasmid gene therapy for therapeutic angiogenesis by J. Isner this approach was an attractive option for ischemic diseases affecting large cohorts of patients. However, first placebo-controlled clinical trials showed its limited efficacy questioning further advance to practice. Thus, combined methods using delivery of several angiogenic factors got into spotlight as a way to improve outcomes. This study provides experimental proof of concept for a combined approach using simultaneous delivery of VEGF165 and HGF genes to alleviate consequences of myocardial infarction (MI). However, recent studies suggested that angiogenic growth factors have pleiotropic effects that may contribute to outcome so we expanded focus of our work to investigate potential mechanisms underlying action of VEGF165, HGF and their combination in MI. Briefly, Wistar rats underwent coronary artery ligation followed by injection of plasmid bearing VEGF165 or HGF or mixture of these. Histological assessment showed decreased size of post-MI fibrosis in both—VEGF165- or HGF-treated animals yet most prominent reduction of collagen deposition was observed in VEGF165+HGF group. Combined delivery group rats were the only to show significant increase of left ventricle (LV) wall thickness. We also found dilatation index improved in HGF or VEGF165+HGF treated animals. These effects were partially supported by our findings of c-kit+ cardiac stem cell number increase in all treated animals compared to negative control. Sporadic Ki-67+ mature cardiomyocytes were found in peri-infarct area throughout study groups with comparable effects of VEGF165, HGF and their combination. Assessment of vascular density in peri-infarct area showed efficacy of both–VEGF165 and HGF while combination of growth factors showed maximum increase of CD31+ capillary density. To our surprise arteriogenic response was limited in HGF-treated animals while VEGF165 showed potent positive influence on a-SMA+ blood vessel density. The latter hinted to evaluate infiltration of monocytes as they are known to modulate arteriogenic response in myocardium. We found that monocyte infiltration was driven by VEGF165 and reduced by HGF resulting in alleviation of VEGF-stimulated monocyte taxis after combined delivery of these 2 factors. Changes of monocyte infiltration were concordant with a-SMA+ arteriole density so we tested influence of VEGF165 or HGF on endothelial cells (EC) that mediate angiogenesis and inflammatory response. In a series of in vitro experiments we found that VEGF165 and HGF regulate production of inflammatory chemokines by human EC. In particular MCP-1 levels changed after treatment by recombinant VEGF, HGF or their combination and were concordant with NF-κB activation and monocyte infiltration in corresponding groups in vivo. We also found that both–VEGF165 and HGF upregulated IL-8 production by EC while their combination showed additive type of response reaching peak values. These changes were HIF-2 dependent and siRNA-mediated knockdown of HIF-2α abolished effects of VEGF165 and HGF on IL-8 production. To conclude, our study supports combined gene therapy by VEGF165 and HGF to treat MI and highlights neglected role of pleiotropic effects of angiogenic growth factors that may define efficacy via regulation of inflammatory response and endothelial function.

DOI ↗ PDF ↗

Plasmid-based gene therapy with hepatocyte growth factor stimulates peripheral nerve regeneration after traumatic injury

2018 · ARTICLE · en

Peripheral nerve injury remains a common clinical problem with no satisfactory treatment options. Numerous studies have shown that hepatocyte growth factor (HGF) exerts neurotrophic effect in motor, sensory, and parasympathetic neurons in addition to mitogenic, morphogenic, angiogenic, antiapoptotic, antifibrotic, and anti-inflammatory effect on various tissues and cells. In our study we examined efficacy of gene therapy with HGF-bearing plasmid (pC4W-hHGF) to improve consequences of traumatic nerve injury in mice. Treatment by pC4W-hHGF led to restoration of nerve structure and functional recovery compared to similar parameters in control animals. Compound action potentials (CAP) in experimental groups treated with 100 or 200 μg of pC4W-hHGF demonstrated increased amplitude and latency decrease compared to spontaneous recovery control group. In HGF-treated mice histological analysis showed a three-fold increase in axon number in nerve portion located distal to the lesion site compared to control. Moreover, significant functional recovery of n. peroneus communis triggered by pC4W-hHGF gene therapy was observed using the footprints analysis. Obtained results provide evidence for plasmid-based HGF gene therapy as a potential treatment for traumatic injury of peripheral nerve.

DOI ↗ PDF ↗

C-Kit Cardiac Progenitor Cell Based Cell Sheet Improves Vascularization and Attenuates Cardiac Remodeling following Myocardial Infarction in Rats

2018 · ARTICLE · en

The adult heart contains small populations of multipotent cardiac progenitor cells (CPC) that present a convenient and efficient resource for treatment of myocardial infarction. Several clinical studies of direct CPC delivery by injection have already been performed but showed low engraftment rate that limited beneficial effects of procedure. «Cell sheet» technology has been developed to facilitate longer retention of grafted cells and show new directions for cell-based therapy using this strategy. In this study we hypothesized that bPC-based cell sheet transplantation could improve regeneration after myocardial infarction.We demonstrated that c-kit+ CPC were able to formcell sheets on temperature-responsive surfaces. Cell sheet represented a well-organized structure, in which CPC survived, retained ability to proliferate, expressed progenitor cellmarker Gata-4 formed connexin-43+ gap junctions, and were surrounded by significant amount of extracellular matrix proteins. Transplantation of cell sheets after myocardial infarction resulted in CPC engraftment as well as their proliferation, migration, and differentiation; cell sheets also stimulated neovascularization and cardiomyocyte proliferation in underlining myocardium and ameliorated left ventricular remodeling. Obtained data strongly supported potential use of CPC sheet transplantation for repair of damaged heart.

DOI ↗ PDF ↗

Cell Sheets from Adipose-Derived Mesenchymal Stromal Accelerate Healing and Angiogenesis

2018 · ARTICLE · en

Cell sheet (CS) technology has advantages for application in regenerative medicine as far as it allows effective and feasible delivery cells for therapeutic application.Cell sheets are minimal tissueengineered constructs that consist of viable cells and extracellular matrix proteins forming a solid multilayered structure. Their expressed therapeutic potential relies on better survival after delivery compared to injection of dispersed cells. This approach has been in our field of interest during last years and we have developed CS application from adult stem cells - mesenchymal (MSC) and c-kit+ cardiac stem cells (CSC) for stimulation of angiogenesis in ischemic skeletal muscle and infarcted myocardium, induction of wound healing and other clinically relevant models. Starting from wound healing in a rat model of deep defect of soft tissues we found that delivery of constructs from adipose-derived MSC significantly accelerated wound healing compared to suspended cells accompanied by higher engraftment rate of CS-delivered MSC compared to dispersed.We also successfully adopted the concept of gene delivery application to modify cells for sake of new therapeutic methods. Using viral delivery of growth factors allows to enhance MSC paracrine and regenerative potential for increased efficacy and better safety. Mostly, these methods utilize the crucial role of paracrine stimuli generated by stem cells during tissue repair or regeneration. Over last decade we have been elaborating to develop strategies using viral vectors to increase production of growth factors and “tune-up” the cells pro-regenerative capacity. Using adenoassociated viruses (AAV) and baculovirus we managed express growth factors in MSC and CSC. Developed methods of viral delivery to express VEGF165 allowed to increase pro-angiogenic potential of cells and induce effective angiogenesis in ischemic tissue of experimental animals rendering effect that was significantly higher compared to GFP-treated or un-modified cells. Indeed, using nude mice to evaluate human MSC impact on recovery of blood flow, we found that VEGFexpressing MSCs had better survival and resulted in higher perfusion and blood vessel counts at experiment’s endpoint.However, viral modification of constructs resulted in even better functional outcome in animal models of ischemia compared to untreated cells or injected dispersed. Furthermore, a large subset of data was obtained indicating graft/host interactions, vascularization of implanted construct and limited cell proliferation within the tissue layer. Overall our set of studies summarizes efforts to develop a next-level cell therapeutic combining feasible and effective delivery technique with viral modification as a way to enhance paracrine modality known to be crucial for MSC and their regenerative potential in numerous lesions affecting human population. Study was supported by RFBR grant #17-04-01452 (cell culture and in vitro assays), partially- by RSF grant #16-45-03007 (animal test and histology) and used biomaterial biomaterial collected and preserved in the frame of the project “Scientific basis for national bank-depositary of living systems” (RSF agreement #14-50-00029) using the equipment purchased as a part of Lomonosov Moscow State University Program of Development.

DOI ↗

Курсы (2)