vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-24-78vavilov-4343Research ArticleМОЛЕКУЛЯРНАЯ И КЛЕТОЧНАЯ БИОЛОГИЯMOLECULAR AND CELL BIOLOGYКонцепция природной реконструкции генома. Часть 1. Основные положения концепции природной реконструкции генома. Изменение генома гемопоэтических стволовых клеток с использованием нескольких природных клеточных механизмов, имманентно присущих гемопоэтической стволовой клетке и определяющих ее биологический статус как «источник репаративного потенциала организма»The concept of natural genome reconstruction. Part 1. Basic provisions of the “natural genome reconstruction” concept. Changing the genome of hematopoietic stem cells using several natural cellular mechanisms that are inherent in the hematopoietic cell and determine its biological status as “the source of the body’s reparative potential”ЯкубовЛ. А.YakubovL. A.https://orcid.org/0000-0002-6746-8092ТарановО. С.TaranovO. S.

р. п. Кольцово, Новосибирская область

Novosibirsk

СидоровС. В.SidorovS. V.

Новосибирск

Novosibirsk

НиконовС. Д.NikonovS. D.

Новосибирск

Novosibirsk

https://orcid.org/0000-0001-6895-938XОстанинА. А.OstaninA. A.

Новосибирск

Novosibirsk

https://orcid.org/0000-0003-2346-6279ЧерныхЕ. Р.ChernykhE. R.

Новосибирск

Novosibirsk

https://orcid.org/0000-0001-6800-8787КолчановН. А.KolchanovN. A.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-2019-9382БогачевС. С.BogachevS. S.

Новосибирск

Novosibirsk

labmolbiol@mail.ruГосударственный научный центр вирусологии и биотехнологии «Вектор» РоспотребнадзораРоссияState Scientific Center of Virology and Biotechnology “Vector” of Rospotrebnadzor, KoltsovoRussian FederationГородская клиническая больница № 1РоссияCity Clinical Hospital No. 1Russian FederationНовосибирский научно-исследовательский институт туберкулезаРоссияNovosibirsk Tuberculosis Research InstituteRussian FederationНаучно-исследовательский институт фундаментальной и клинической иммунологииРоссияResearch Institute of Fundamental and Clinical ImmunologyRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian Federation202421112024287696705Copyright © Якубов Л.А., Таранов О.С., Сидоров С.В., Никонов С.Д., Останин А.А., Черных Е.Р., Колчанов Н.А., Богачев С.С., 20242024Якубов Л.А., Таранов О.С., Сидоров С.В., Никонов С.Д., Останин А.А., Черных Е.Р., Колчанов Н.А., Богачев С.С.Yakubov L.A., Taranov O.S., Sidorov S.V., Nikonov S.D., Ostanin A.A., Chernykh E.R., Kolchanov N.A., Bogachev S.S.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4343

Предлагается вниманию цикл статей, доказывающий существование ранее неизвестного механизма взаимодействия гемопоэтической стволовой клетки и экстраклеточной двуцепочечной ДНК (в частности, двуцепочечной ДНК периферического кровяного русла), который объясняет возможность появления и закрепления в гемопоэтических стволовых клетках генетической информации, содержащейся в двуцепочечной ДНК внеклеточного происхождения. Сформулирована концепция возможности стохастического или целенаправленного изменения генома гемопоэтических стволовых клеток, основанная на открытии новых, ранее неизвестных биологических свойств низкодифференцированных гемопоэтических предшественников. Основные положения концепции заключаются в следующих тезисах. Гемопоэтическая стволовая клетка захватывает и интернализует фрагменты экстраклеточной двуцепочечной ДНК естественным природным механизмом. В акте интернализации принимают участие специфические группы факторов гликокаликса, к которым относятся гликопротеины/ протеогликаны, гликозилфосфатидилинозитол-заякоренные белки и скавенджер-рецепторы. Сайтами связывания фрагментов ДНК являются гепарин-связывающие домены и кластеры положительно заряженных аминокислотных остатков, входящих в состав белковых молекул указанных факторов. Доставленные во внутренние компартменты гемопоэтических стволовых клеток экстраклеточные фрагменты инициируют терминальную дифференцировку, колониеобразование и пролиферацию предшественников гемопоэза. Молекулярным событием, отражающим эти процессы, является возникновение и репарация пангеномных одноцепочечных разрывов. Процесс возникновения пангеномных одноцепочечных разрывов и восстановление целостности генома (геномной ДНК) сопряжен с активацией в клетке «рекомбиногенной ситуации», во время активной фазы которой возможны стохастическая гомологичная рекомбинация или иные рекомбинационные события между экстраклеточными фрагментами, локализованными в ядре, и ДНК хромосом. Генетический материал исходно экстраклеточной локализации или интегрирует в реципиентный геном с замещением гомологичных хромосомных сегментов, или транзитно присутствует в ядре и может проявляться как новый генетический признак. Предполагается, что в результате стохастических актов гомологичного обмена происходит коррекция локусов хромосом в гемопоэтических стволовых клетках, получивших в ходе существования организма мутации, которые являются причиной клонального гемопоэза, ассоциированного со старостью. В этой связи возникает принципиальная возможность изменения статуса гемопоэза гемопоэтических стволовых клеток в направлении поликлональности и исходного многообразия клонов. Такие события могут составить основу омоложения кровеобразующей системы клеток. Результаты работ свидетельствуют, что другие стволовые клетки организма также захватывают фрагменты экстраклеточной ДНК. Этот факт создает парадигму общего омоложения организма.

We present a series of articles proving the existence of a previously unknown mechanism of interaction between hematopoietic stem cells and extracellular double-stranded DNA (and, in particular, double-stranded DNA of the peripheral bloodstream), which explains the possibility of emergence and fixation of genetic information contained in double-stranded DNA of extracellular origin in hematopoietic stem cells. The concept of the possibility of stochastic or targeted changes in the genome of hematopoietic stem cells is formulated based on the discovery of new, previously unknown biological properties of poorly differentiated hematopoietic precursors. The main provisions of the concept are as follows. The hematopoietic stem cell takes up and internalizes fragments of extracellular double-stranded DNA via a natural mechanism. Specific groups of glycocalyx factors, including glycoproteins/proteoglycans, glycosylphosphatidylinositol-anchored proteins and scavenger receptors, take part in the internalization event. The binding sites for DNA fragments are heparin-binding domains and clusters of positively charged amino acid residues that are parts of protein molecules of these factors. Extracellular fragments delivered to the internal compartments of hematopoietic stem cells initiate terminal differentiation, colony formation, and proliferation of hematopoietic precursors. The molecular manifestation of these processes is the emergence and repair of pangenomic single-strand breaks. The occurrence of pangenomic single-strand breaks and restoration of genome (genomic DNA) integrity are associated with activation of a “recombinogenic situation” in the cell; during its active phase, stochastic homologous recombination or other recombination events between extracellular fragments localized in the nucleus and chromosomal DNA are possible. As a result, genetic material of initially extracellular localization either integrates into the recipient genome with the replacement of homologous chromosomal segments, or is transitively present in the nucleus and can manifest itself as a new genetic trait. It is assumed that as a result of stochastic acts of homologous exchange, chromosome loci are corrected in hematopoietic stem cells that have acquired mutations during the existence of the organism, which are the cause of clonal hematopoiesis associated with old age. In this regard, there is a fundamental possibility of changing the hematopoietic status of hematopoietic stem cells in the direction of polyclonality and the original diversity of clones. Such events can form the basis for the rejuvenation of the blood-forming cell system. The results of the laboratory’s work indicate that other stem cells in the body capture extracellular DNA fragments too. This fact creates a paradigm for the overall rejuvenation of the body.

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