Черепно-мозговая травма: основные клеточные механизмы и новые подходы к терапии

Обложка

Цитировать

Полный текст

Аннотация

Черепно-мозговая травма (ЧМТ) представляет серьезную медицинскую проблему и является одной из ведущих причин инвалидности и смертности среди военнослужащих и гражданского населения. Известно, что ежегодно в мире от ЧМТ погибает порядка 1,5 млн человек, при этом около 2,5–3 млн теряют трудоспособность. В России каждый год ЧМТ диагностируется у 1 млн человек, среди которых каждый пятый становится инвалидом I или II группы. Несмотря на значительные усилия в области исследований эффективные методы лечения ЧМТ до сих пор остаются ограниченными, так как ЧМТ характеризуется широким спектром патологических изменений в тканях головного мозга. Первичное повреждение головного мозга представляет собой острое и необратимое механическое повреждение паренхимы нервной ткани. Последующие процессы вторичного включают в себя эксайтотоксичность, митохондриальную дисфункцию, окислительный стресс, дегенерацию аксонов и нейровоспаление. Эти процессы часто растягиваются во времени и могут занимать от нескольких дней до нескольких лет. Недавние достижения в области клеточной терапии открывают новые перспективы для терапии этого состояния. В данном обзоре рассмотрены основные клеточные механизмы острой и хронической фаз ЧМТ, а также перспективы применения стволовых клеток для терапии данного заболевания. Представлен анализ последних исследований, посвященных применению клеточной терапии при ЧМТ. Рассматриваются различные типы стволовых клеток, такие как нейральные стволовые клетки, мезенхимальные стромальные клетки и другие в контексте их потенциала для восстановления поврежденных тканей мозга. Особое внимание уделяется механизмам действия клеток в процессе регенерации, включая их влияние на воспаление, нейрогенез, и синаптическую пластичность. Рассматривается использование паракринных факторов, выделяемых стволовыми клетками, в качестве потенциального препарата для терапии черепно-мозговых травм. Выводы. Клеточная терапия, а также использование продуктов, секретируемыми клетками, являются новыми и многообещающими способами лечения ЧМТ.

Полный текст

Introduction

Traumatic brain injury (TBI) pathogenesis is a complex process resulting from primary and secondary injuries leading to temporary or permanent neurological deficits. The blow results in primary damage (acute phase), expressed by a mechanical violation of endothelial cells, neurons and glia integrity. Secondary damage develops in a time interval from several minutes to several days after the primary damage due to the activation of various cascades leading to further brain damage. Damaged cells produce a large number of factors: ions, proteins, signaling molecules that initiate inflammation, apoptosis and oxidative stress processes in the surrounding tissues. The acute phase lasts about 24 hours. After that, the activation of the pro-inflammatory phenotype of microglia (M1) and reactive astrocytes, as well as blood-­brain barrier (BBB) damage and the involvement of peripheral immune cells trigger chronic neuroinflammation mechanisms. The chronic phase is long-term [1–4].

Cell therapy is a promising approach in TBI treatment. This method is aimed at restoring damaged brain tissues and improving functions, and has a positive effect on various cellular processes. The use of stem cells, including neural stem cells and mesenchymal stromal cells, is one of the challenging areas, since they have the ability to differentiate into various cell types, which can help replace damaged neurons and maintain cellular homeostasis. At the same time, cell therapy can stimulate regeneration mechanisms, including neurogenesis (formation of new neurons), angiogenesis (formation of new vessels) and synaptogenesis (formation of new synapses). These processes contribute to the restoration of the brain damaged areas functions. Also, stem cells secrete anti-inflammatory factors, which can have an anti-inflammatory effect, reducing the activation of microglia and astrocytes, as well as reducing the levels of cytokines and other inflammatory mediators.

Cellular response to TBI

A large number of cells are activated in TBI in response to brain damage. Astrocytes, oligodendrocytes, NG2+ precursors of oligodendrocytes, neural stem cells (NSCs) and ependymal cells of the ventricular membrane of the brain are the first to react to the destruction of nervous tissue. In addition, the response also occurs in non-neural CNS cells, namely — in microglial cells, perivascular phagocytes, pericytes and endothelial cells. Blood cells such as leukocytes, platelets, fibroblasts and mesenchymal precursors are attracted to the site of inflammation [2].

Mechanical action on brain cells leads to stretched neuronal membranes, their depolarization and influx of calcium ions (Ca2+). In addition, diffuse axon damage (traumatic axon shift), leads to bending and disintegration of microtubules (MTB). As a result, the occurring structural damage causes disruption of axonal transport, swelling of axons and, subsequently, their degradation [3, 4]. In mild TBI, small cell damage contributes to a slight increase in extracellular concentrations of glutamate and/or ATP. This, in turn, helps to attract microglia without developing an inflammatory reaction. In addition, extracellular ATP can interact with astrocytes, leading to an increase in intracellular Ca2+ and the release of astrocytic ATP through connexins, which increases the possibility of an inflammatory reaction.
Significant disturbances and cell death stimulate the release of cytosolic and nuclear contents: DNA, RNA, potassium (K+), heat shock proteins, and calcium-­binding proteins of the S100 family [2]. Subsequent development of inflammation is associated with the release of a large number of neurotransmitters, cytokines and chemokines, which stimulate the activation of glial cells (so-called reactive gliosis), microglia and attract immune cells (Fig.1) [5].

Activation of microglia

Microglia is an important component of the brain immune defense. Normally, M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes of microglia work in tandem, supporting both the processes of destruction (removal of damaged cells) and restoration of nervous tissue. In response to various cytokines, especially in response to interleukin‑1β (IL‑1β) and interleukin‑18 (IL‑18), secreted both by damaged cells and by the microglia itself, changes occur in the morphology and functional activity of the microglia, as a result of which the latter acquires the M1 phenotype. As a result, the NF-kB signaling pathway and the pathways of mitogen-­activated protein kinases (MAPK) are activated in microglial cells. This leads to M1‑microglia starting to secrete a large number of such proinflammatory cytokines as IL‑1β, interleukin‑6 (IL‑6), interleukin‑8 (IL‑8), IL‑18, interferon-γ (IFNy) and tumor necrosis factor-α (TNFa, or TNF-α). In addition, M1‑microglia has high phagocytic activity: it can mediate the metabolism of extracellular phosphatidylinositol as a source of arachidonic acid for the synthesis of leukotriene [4, 6, 7]. At the same time, M1 microglia can enhance oxidative stress by increasing the expression of NADPH oxidase and inducible NO synthase (iNOS) [8, 9].

It is important to note that during TBI, M2 phenotype of microglia which has three subtypes: M2a, M2b and M2c, is also activated. Activation of M2‑microglia most often occurs later than activation of M1‑microglia, and can be induced by interleukin‑4 (IL‑4). It is very important that in response to TBI, the activation of M1 macrophages quickly transitions into a recovery reaction due to the activation of M2 phenotype [10]. To date, it is known that microglia of M2a subtype inhibits inflammation processes, and also stimulates cell proliferation and migration to the site of injury, where it is able to increase the expression of the antagonist of the IL‑1 receptor, arginase‑1 and the trigger receptor expressed on myeloid cells‑2 (TREM2). M2b microglia, in turn, has both pro-inflammatory and anti-inflammatory functions. The expression of IL‑1, TNFa, IL‑6 and Toll-like receptors (TLRs) is associated with its pro-inflammatory activity, and the expression of arginase‑1 is associated with anti–inflammatory activity. At the same time, M2c subtype exhibits anti-inflammatory activity due to the high level of expression of transforming growth factor-β (TGFß), CD206, CD163 and sphingosine kinase‑1 [8]. In addition, it has been shown that M2 microglia is able to secrete insulin-like growth factor‑1 (IGF‑1), which has a positive trophic effect. M2 microglia is also capable of producing nerve growth factor (NGF), brain neurotrophic factor (BDNF) and neurotrophin‑3 (NT‑3), which stimulate neurons growth and survival [10].

Reactive gliosis

Under normal physiological conditions, glial cells support the functions of neurons, influence neuroglial interactions, and participate in maintaining neurotransmitters synaptic connections and balance. In pathological conditions, the situation is different, in particular, in TBI, the presence of numerous cytokines initiates reactive gliosis. The interaction of astrocyte receptors with IL‑1β, TNF-α, and TGF‑1β causes morphological and functional changes in cells: astrocytes become hypertrophied, demonstrating noticeable changes in the level of certain proteins (for example, glial fibrillar acid protein (GFAP), intermediate filaments, vimentin and nestin). The influence of reactive glial cells on the surrounding cells that support normal functioning of neurons can lead to synapse defects, impaired secretion of neurotransmitters and neuronal death. It is generally believed that reactive astrocytes are localized at the site of injury, however, there is evidence describing their ability to migrate to healthy tissues [10, 11]. It is important to note that reactive astrocytes are capable of forming a glial scar (astrocytic scar), which borders the site of injury. On the one hand, scar formation is needed for partial separation of damaged tissue from healthy tissue in order to prevent widespread inflammation; on the other hand, neurogenesis and neurodevelopment processes are often suppressed in the scar area, because the scar forms a structural barrier that constantly secretes axon growth inhibitors [2, 10, 12, 13].

The regulation of reactive gliosis occurs not only due to proinflammatory agents and various molecules produced by damaged cells, but also due to the influence of substances capable of penetrating through the damaged BBB; substances secreted by leukocytes, as well as due to paracrine and autocrine factors. Reactive glial cells specifically alter the expression of different genes, both depending on the activating molecular cascades, and on the type of injury and severity of damage [2].

Involvement of peripheral immune cells

Focal brain injuries exhibit a characteristic inflammatory response with infiltration by peripheral immune cells after injury. It is believed that these cells are important because they are able to secrete many inflammatory mediators associated with increased tissue damage. In addition, a large amount of data obtained in the study of ischemic injuries indicates that inhibition of leukocyte recruitment contributes to a decreased affected area and the development of a favorable outcome [14].

Activation of endogenous neural stem cells

As is known, there are two main localization zones of neural stem cells in the human and rodent brains: the subventricular zone surrounding the lateral ventricles and the subgranular zone of the dentate gyrus of the hippocampus. The latter is especially important for the formation of new neurons and new synapses in already existing neural circuits. In addition, modeling TBI in rodents showed activation of NSCs of the hippocampus subgranular zone. At the same time, an increase in the level of NSCs proliferation, formation of new neurons and their migration to the site of injury is observed. Literature data analysis shows that in TBI the largest number of neurons is formed in the hippocampus, which is especially important for cognitive functions restoration. However, the problem of effective restoration of nervous tissue in TBI is that the survival rate of newly formed neurons is quite low, especially in conditions of progressive neuroinflammation and apoptosis of surrounding cells. Thus, in order to start the process of endogenous brain repair, it is necessary to use a strategy aimed at stimulating the proliferation of NSCs, increasing the survival of neurons and their migration to damaged areas of the brain (Fig. 1) [15].

New approaches to TBI therapy

Currently, the use of stem cells in regenerative medicine is a promising and challenging area. For more than 30 years, the topic of cell transplantation has been actively studied in order to further apply such technology in TBI treatment. To date, two main hypotheses of the effectiveness of such treatment are described. According to the first one, the transplanted cells have the ability to differentiate into functionally active neurons and glial cells in the lesion, thereby contributing to the restoration of damaged tissue integrity and functionality. According to the second, cells produce various factors, which, in turn, contribute to the inhibition of tissue degeneration, stimulate the restoration of the microenvironment of the damaged central nervous system and regeneration [16]. Literature describes the use of NSC, iPSC and MSC for TBI treatment. Preclinical studies also confirmed the effectiveness of the use of any of the above-­mentioned cell types [17].

Loss of functionally active nerve tissue is the most common injury in TBI. Given the limited population of endogenous NSCs, transplantation of exogenous stem cells into damaged areas of the brain is a truly promising method of TBI therapy [15]. It is known that the implantation of NSCs in the central nervous system stimulates the processes of neurogenesis and regeneration of damaged tissue. Transplanted NSCs are able to self-renew and differentiate into neurons, astrocytes and oligodendrocytes. At the same time, obtained neurons take an active part in the restoration of nervous tissue, while astrocytes and oligodendrocytes are involved in the processes of remyelination, maintaining trophic function and stimulating the restoration of the surrounding neural cells. Improvement of cognitive functions during NSC transplantation is associated with increased synaptogenesis. Implanted NSCs are also able to enhance angiogenesis by increasing the expression of vascular endothelial growth factor (VEGF), reduce astrogliosis and proinflammatory cytokines secretion [18].

Fig. 1. Cellular response to damage caused by TBI. The red arrows show autocrine and paracrine effects, the blue arrows show the effects of astrocytes and microglia on neurons, according to Chiu et al., 2016, modified [10]

Today, embryonic stem cells are considered a promising source for the treatment of various diseases, due to the cells’ high plasticity, their ability to differentiate into all three germ sheets (endoderm, mesoderm and ectoderm) and to unlimited self-renewal [19]. One study demonstrated a decrease in the volume of the damaged area, astrogliosis decrease and motor functions improvement during transplantation of embryonic NSCs to rats in a TBI model [20]. In addition, it is interesting to note that human NSCs (hNSC) transplanted to immunodeficient rats are able to survive for six months after administration, differentiating into mature neurons, astrocytes and oligodendrocytes. It is assumed that hNSC transplantation can become an effective therapy for the restoration of cognitive functions after brain injury [21].

As is known, the use of embryonic materials in cell therapy is undesirable for ethical reasons; therefore, special attention of scientists in recent years has been focused on the study of iPSCs. To obtain iPSCs from somatic cells, the technique described by Yamanaka’s group in 2006 is most often used [17, 22]. It is important that iPSCs have a high proliferative potential and are able to give rise to all three germ leaves. It is equally important that iPSCs are ideal candidates for autologous cell therapy, because they can be obtained individually, directly from patients. All this makes it possible to avoid both problems related to immune rejection of the transplant and ethical problems [15]. Literature describes studies where IPSC cell therapy helps to improve motor activity and restore cognitive function in TBI [23, 24]. Nevertheless, the use of iPSCs in cell therapy has its limitations, which are associated with high tumorigenicity, difficulty of obtaining iPSCs and high cost of therapy [16, 17].

As recent studies have shown, MSCs also have potential in the treatment of TBI, due to their anti-inflammatory and anti-apoptotic properties. MSCs are multipotent stem cells with the ability to self-renew and multi-­differentiate. Since they are present in many tissues of our body, they can be isolated from various sources: bone marrow, skeletal muscles, adipose tissue, and peripheral blood. In different microenvironments, MSCs differentiate into mesodermal cells and tissues. It is known that MSCs have a number of advantages, the main of which are their easy production, low immunogenicity, high regenerative potential even after freezing, as well as their ability to migrate to the lesion site. These characteristics make MSCs a promising tool for TBI therapy [25]. Studies have shown that when MSCs are transplanted directly into the injury area or using intravenous or intraarterial injections during the acute, subacute or chronic phases of TBI, there is a significant decrease in neurological deficits of motor and cognitive functions [15, 26]. In addition, clinical trials on the use of MSCs as TBI therapy demonstrated that MSCs contribute to the regeneration of brain tissue [27] and improve motor functions [28].

The introduction of stem cells directly into the lesion is an extremely difficult process, which is associated with the complexity of the delivery procedure itself and the risks of systemic side effects. At the same time, the disadvantages of intravenous and intraarterial administration are high risks of a generalized immune response [29].

To date, there is increasing evidence indicating the importance of paracrine signaling by transplanted cells as a mechanism supporting the repair of damaged tissues. That is why the focus of research has shifted to the use of products secreted by stem cells: neurotrophic factors, complexes of biologically active molecules obtained from conditioned media, or extracellular vesicles. This approach avoids both ethical problems of cell transplantation and the problems associated with immune rejection of the injected material [19, 30, 31].
It is interesting to consider the use of the secretome and extracellular vesicles (EV) of stem cells in TBI therapy. There is evidence from literature sources that, for example, in the pig TBI model, the use of extracellular vesicles produced by human MSCs (MSC-EV) helps to reduce edema and partially restore the integrity of the blood-­brain barrier [32]. While in the rat model of TBI, the use of MSC-EV improves cognitive and sensorimotor functions, reduces neuroinflammation and death of hippocampal neurons. At the same time, there is a significant increase in the population of endothelial cells in the damaged area, as well as an increase in the number of new immature neurons in the dentate gyrus of the hippocampus, which emphasizes the involvement of EV in the induction of angiogenesis and neurogenesis [33, 34]. In addition, it is known that nanoscale membrane vesicles of MSCs, called exosomes, are capable of having anti-apoptotic, immunomodulatory and neuroprotective effects. The latter, in particular, is due to the induction of the transformation of the proinflammatory phenotype of microglia into an anti-inflammatory one, which is largely due to a decrease in the level of IL‑1β [35]. It is important to note that MSC secretome also has a therapeutic effect, which was demonstrated in a rat model of TBI. It has been shown that MSC secretome has an anti-inflammatory effect, due to switching of M1 microglia phenotype to M2, which, in turn, is associated with interleukin‑10 (IL‑10), being part of the secretome [36].

Literature describes positive paracrine effect not only of MSCs, but also of other types of stem cells. For example, it is known that intravenous administration of extracellular vesicles of NSC (NSC-EV) to rats with TBI has a neuroprotective effect, promotes restoration of motor function in animals and migration of endogenous NSCs to the lesion [37]. At the same time, the effect of the use of NSC-EV is sex-dependent: males have a much more pronounced therapeutic effect than females [38]. In addition, it is known that NSC exosomes are able to penetrate the blood-­brain barrier, inhibit apoptosis, suppress inflammation and regulate autophagy [39]. It has been shown that the target of miR‑1246 microRNA included in NSC exosomes is the p53 protein, which, in turn, takes an active part in the regulation of apoptosis and the cell cycle [39, 40]. MiR‑21a, another microRNA of NSC exosomes, initiates cell differentiation and promotes regeneration of nervous tissue [41]. In addition to the above, it has been demonstrated that the use of NSC exosomes leads to a decreased affected area of the brain in the rat model of TBI and activates the process of angiogenesis, which is especially noticeable in males [37].

Conclusion

TBI is an important medical problem with serious consequences for health and quality of life. TBI triggers complex cellular mechanisms, including activation of various cell types. Traumatic exposure provokes microglia and astrocytes activation, which leads to the secretion of cytokines, interleukins and other inflammatory mediators. TBI activates a systemic inflammatory response, which is accompanied by the migration of leukocytes, such as neutrophils and monocytes, to the injury area. At the same time, damaging effects can initiate the proliferation of neural stem cells in certain areas of the brain, which can contribute to the formation of new neurons and maintain brain plasticity.

Despite significant advances in the diagnosis and primary therapy of TBI, rehabilitation and recovery methods are still not effective enough. Cell therapy is a promising approach aimed at regenerative processes and restoration of brain functions. However, despite the prospects, additional research is needed to optimize the use of cell therapy in clinical practice. The issues of safety, efficacy and selection of suitable cellular sources require further research.

Summarizing all the above, it can be noted that today profound knowledge of the cellular and molecular processes underlying the pathogenesis of TBI, allows us to consider direct cell transplantation and the use of products secreted by them as a promising method of TBI therapy.

×

Об авторах

А. К. Судьина

Российский университет дружбы народов; Медико-генетический научный центр им. Н.П. Бочкова

Автор, ответственный за переписку.
Email: sudyina-ak@rudn.ru
ORCID iD: 0000-0003-3531-7684
SPIN-код: 5225-7878
г. Москва, Российская федерация

Л. Р. Гринчевская

Российский университет дружбы народов; Медико-генетический научный центр им. Н.П. Бочкова

Email: sudyina-ak@rudn.ru
ORCID iD: 0009-0008-5850-8460
г. Москва, Российская федерация

Д. В. Гольдштейн

Российский университет дружбы народов; Медико-генетический научный центр им. Н.П. Бочкова

Email: sudyina-ak@rudn.ru
ORCID iD: 0000-0003-2438-1605
SPIN-код: 7714-9099
г. Москва, Российская федерация

Т. Х. Фатхудинов

Российский университет дружбы народов; Медико-генетический научный центр им. Н.П. Бочкова

Email: sudyina-ak@rudn.ru
ORCID iD: 0000-0002-6498-5764
SPIN-код: 7919-8430
г. Москва, Российская федерация

Д. И. Салихова

Российский университет дружбы народов; Медико-генетический научный центр им. Н.П. Бочкова

Email: sudyina-ak@rudn.ru
ORCID iD: 0000-0001-7842-7635
SPIN-код: 1436-5027
г. Москва, Российская федерация

Список литературы

  1. Burton D, Aisen M. Traumatic Brain Injury. Handbook of Secondary Dementials. 2006;26(7): 83-118. doi: 10.1177/0963689717714102
  2. Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron. 2014;81(2):229-248. doi: 10.1016/j.neuron.2013.12.034
  3. Humble SS, Wilson LD, Wang L, Long DA, Smith MA, Siktberg JC, Mirhoseini MF, Bhatia A, Pruthi S, Day MA, Muehlschlegel S, Patel MB. Prognosis of diffuse axonal injury with traumatic brain injury. The journal of trauma and acute care surgery. 2018;85(1):155-159. doi: 10.1097/TA.0000000000001852
  4. Sulhan S, Lyon KA, Shapiro LA, Huang JH. Neuroinflammation and blood-brain barrier disruption following traumatic brain injury: Pathophysiology and potential therapeutic targets. Journal of neuroscience research. 2020;98(1):19-28. doi: 10.1002/jnr.24331
  5. Lu J, Goh SJ, Lei Tng YL, Deng YY, Ling EA, Moochhala S. Systemic inflammatory response following acute traumatic brain injury. Frontiers in bioscience (Landmark edition). 2009;14(10):3795-3813. doi: 10.2741/3489
  6. Beschorner R, Nguyen TD, Gözalan F, Pedal I, Mattern R, Schluesener HJ, Meyermann R, Schwab JM. CD14 expression by activated parenchymal microglia/macrophages and infiltrating monocytes following human traumatic brain injury. Acta neuropathologica. 2002;103(6)541-549. doi: 10.1007/s00401-001-0503-7
  7. Xiong Y, Mahmood A, Chopp M. Current understanding of neuroinflammation after traumatic brain injury and cell-based therapeutic opportunities. Chinese journal of traumatology. 2018;21(3):137-151. doi: 10.1016/j.cjtee.2018.02.003
  8. Bergold PJ. Treatment of traumatic brain injury with anti-inflammatory drugs. Experimental neurology. 2016;275(3):367-380. doi: 10.1016/j.expneurol.2015.05.024
  9. Wu H, Zheng J, Shenbin X, Fang Y, Wu Y, Zeng J, Shao A, Shi L, Lu J, Mei S, Wang X, Guo X, Wang Y, Zhao Z, Zhang J. Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury. Journal of neuroinflammation. 2021;18(1):1-20. doi: 10.1186/s12974-020-02041-7
  10. Chiu CC, Liao YE, Yang LY, Wang JY, Tweedie D, Karnati HK, Greig NH, Wang JY. Neuroinflammation in animal models of traumatic brain injury. Journal of neuroscience methods. 2016;272:38-49. doi: 10.1016/j.jneumeth.2016.06.018
  11. Brenner M. Role of GFAP in CNS injuries. Neuroscence. Letters. 2014;565:7-13. doi: 10.1016/j.neulet.2014.01.055
  12. Engelmann C, Weih F, Haenold R. Role of nuclear factor kappa B in central nervous system regeneration. Neural regeneration research. 2014;9(7):707-711. doi: 10.4103/1673-5374.131572
  13. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481-487. doi: 10.1038/nature21029
  14. Rhodes J. Peripheral immune cells in the pathology of traumatic brain injury? Current opinion in critical care. 2011;17(2):122-130. doi: 10.1097/MCC.0b013e3283447948
  15. Weston NM, Sun D. The Potential of Stem Cells in Treatment of Traumatic Brain Injury. Current neurology and neuroscience reports. 2018;18(1):1. doi: 10.1007/s11910-018-0812-z
  16. Li X, Sundström. Stem Cell Therapies for Central Nervous System Trauma: The 4 Ws-­What, When, Where, and Why. Stem cells translational medicine. 2022;11(1):14-25. doi: 10.1093/stcltm/szab006
  17. Bonilla C, Zurita M. Cell-based therapies for traumatic brain injury: Therapeutic treatments and clinical trials. Biomedicines. 2021;9(6)1-34. doi: 10.3390/biomedicines9060669
  18. Pang AL, Xiong LL, Xia QJ, Liu F, Wang YC, Liu F, Zhang P, Meng BL, Tan S, Wang TH. Neural stem cell transplantation is associated with inhibition of apoptosis, Bcl-xL upregulation, and recovery of neurological function in a rat model of traumatic brain injury. Cell transplantation. 2017;26(7):1262-1275. doi: 10.1177/0963689717715168
  19. Hentze H, Graichen R, Colman A. Cell therapy and the safety of embryonic stem cell-derived grafts. Trends in biotechnology. 2007;25(1):24-32. doi: 10.1016/j.tibtech.2006.10.010
  20. Narouiepour A, Ebrahimzadeh-­Bideskan A, Rajabzadeh G, Gorji A, Negah SS. Neural stem cell therapy in conjunction with curcumin loaded in niosomal nanoparticles enhanced recovery from traumatic brain injury. Scietific reports. 2022;12(1):1-13. doi: 10.1038/s41598-022-07367-1
  21. Haus DL, López-­Velázquez L, Gold EM, Cunningham KM, Perez H, Anderson AJ, Cummings BJ. Transplantation of human neural stem cells restores cognition in an immunodeficient rodent model of traumatic brain injury. Experimental neurology. 2016;281:1-16. doi: 10.1016/j.expneurol.2016.04.008
  22. Takahashi K, Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell. 2006;126(4):663-676. doi: 10.1016/j.cell.2006.07.024
  23. Dunkerson J, Moritz KE, Young J, Pionk T, Fink K, Rossignol J, Dunbar G, Smith JS. Combining enriched environment and induced pluripotent stem cell therapy results in improved cognitive and motor function following traumatic brain injury. Restorative neurology and neuroscience. 2014;32(5):675-687. doi: 10.3233/RNN-140408
  24. Wei ZZ, Lee JH, Zhang Y, Zhu YB, Deveau TC, Gu X, Winter MM, Li J, Wei L, Yu SP. Intracranial Transplantation of Hypoxia-­Preconditioned iPSC-Derived Neural Progenitor Cells Alleviates Neuropsychiatric Defects after Traumatic Brain Injury in Juvenile Rats. Cell transplantation. 2016;25(5):797-809. doi: 10.3727/096368916X690403
  25. Zhang K, Jiang Y, Wang B, Li T, Shang D, Zhang X. Mesenchymal Stem Cell Therapy: A Potential Treatment Targeting Pathological Manifestations of Traumatic Brain Injury. Oxidative medicine and cellular longevity. 2022;2022. doi: 10.1155/2022/4645021
  26. Силачёв Д.Н., Плотников Е.Ю., Бабенко В.А., Данилина Д.И., Зорова Л.Д., Певзнер И.Б., Зоров Д.Б., Сухих Г.Т. Внутриартериальное введение мультипотентных мезенхимных стромальных клеток усиливает функциональное восстановление головного мозга после черепно- мозговой травмы // Клеточные технологии в биологии и медицине. 2015. № . 2. С. 71-77.
  27. Cox CS, Hetz RA, Liao GP, Aertker BM, Ewing-­Cobbs L, Juranek J, Savitz SI, Jackson ML, Romanowska-­Pawliczek AM, Triolo F, Dash PK, Pedroza C, Lee DA, Worth L, Aisiku IP, Choi HA, Holcomb JB, Kitagawa RS. Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells. Stem Cells. 2017;35(4):1065-1079. doi: 10.1002/stem.2538
  28. Tian C, Wang X, Wang X, Wang L, Wang X, Wu S, Wan Z. Autologous Bone Marrow Mesenchymal Stem Cell Therapy in the Subacute Stage of Traumatic Brain Injury by Lumbar Puncture. Experimental and clinical transplantation: official journal of the Middle East Society for Organ Transplantation. 2013;11(2):176-181. doi: 10.6002/ect.2012.0053
  29. Argibay B. Trekker J, Himmelreich U, Beiras A, Topete A, Taboada P, Pérez-­Mato M, Vieites-­Prado A, Iglesias-­Rey R, Rivas J, Planas AM, Sobrino T, Castillo J, Campo F. Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia. Scietific reports. 2017;7(1):40758. doi: 10.1038/srep40758
  30. Pinho AG, Cibrão JR, Silva NA, Monteiro S, Salgado AJ. Cell secretome: Basic insights and therapeutic opportunities for CNS disorders. Pharmaceuticals. 2020;13(2):1-18. doi: 10.3390/ph13020031
  31. Yang HN, Wang C, Chen H, Li L, Ma S, Wang H, Fu YR, Qu T. Neural stem cell-conditioned medium ameliorated cerebral ischemia-­reperfusion injury in rats. Stem Cells Internetional. 2018;2018:4659159. doi: 10.1155/2018/4659159
  32. Roura S, Monguió-­Tortajada M, Munizaga-­Larroudé M, Clos-­Sansalvador M, Franquesa M, Rosell A, Borràs FE. Potential of extracellular vesicle-­associated TSG-6 from adipose mesenchymal stromal cells in traumatic brain injury. International journal of molecular sciences. 2020;21(18):1-21. doi: 10.3390/ijms21186761
  33. Zhang Y, Zhang Y, Chopp M, Pang H, Zhang ZG, Mahmood A, Xiong Y. MiR-17-92 Cluster-­Enriched Exosomes Derived from Human Bone Marrow Mesenchymal Stromal Cells Improve Tissue and Functional Recovery in Rats after Traumatic Brain Injury. Journal of neurotrauma. 2021;38(11):1535-1550. doi: 10.1089/neu.2020.7575
  34. Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A, Xiong Y. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. Journal of neurosurgery. 2015;122(4):856-867. doi: 10.3171/2014.11.JNS14770
  35. Liu YY, Li Y, Wang L, Zhao Y, Yuan R, Yang MM, Chen Y, Zhang H, Zhou FH, Qian ZR, Kang HJ. Mesenchymal stem cell-derived exosomes regulate microglia phenotypes: a promising treatment for acute central nervous system injury. Neural regeneration research. 2022;18(8):1657-1665. doi: 10.4103/1673-5374.363819
  36. Pischiutta F, Caruso E, Cavaleiro H, Salgado AJ, Loane DJ, Zanier ER. Mesenchymal stromal cell secretome for traumatic brain injury: Focus on immunomodulatory action. Experimental neurology. 2022;357:114199. doi: 10.1016/j.expneurol.2022.114199
  37. Sun MK, Passaro AP, Latchoumane CF, Spellicy SE, Bowler M, Goeden M, Martin WJ, Holmes PV, Stice SL, Karumbaiah L. Extracellular Vesicles Mediate Neuroprotection and Functional Recovery after Traumatic Brain Injury. Journal of neurotrauma. 2020;37(11):1358-1369. doi: 10.1089/neu.2019.6443
  38. Hering C, Shetty AK. Extracellular Vesicles Derived From Neural Stem Cells, Astrocytes, and Microglia as Therapeutics for Easing TBI-Induced Brain Dysfunction. Stem cells translational medicine. 2023;12(3):140-153. doi: 10.1093/stcltm/szad004
  39. Zhong L, Wang J, Wang P, Liu X, Liu P, Cheng X, Cao L, Wu H, Chen J, Zhou L. Neural stem cell-derived exosomes and regeneration: cell-free therapeutic strategies for traumatic brain injury. Stem cell research & therapy. 2023;14(1):198.
  40. Zhang Y, Liao JM, Zeng SX, Lu H. p53 downregulates Down syndrome-­associated DYRK1A through miR-1246. EMBO Reports. 2011;12(8):811-817. doi: 10.1038/embor.2011.98
  41. Ma Y, Li C, Huang Y, Wang Y, Xia X, Zheng JC. Exosomes released from neural progenitor cells and induced neural progenitor cells regulate neurogenesis through miR-21a. Cell communication and signaling: CCS. 2019;17(1):96. doi: 10.1186/s12964-019-0418-3

Дополнительные файлы

Доп. файлы
Действие
1. JATS XML
Скачать
2. Fig. 1. Cellular response to damage caused by TBI. The red arrows show autocrine and paracrine effects, the blue arrows show the effects of astrocytes and microglia on neurons, according to Chiu et al., 2016, modified [10]

Скачать (128KB)
Метаданные

© Судьина А.К., Гринчевская Л.Р., Гольдштейн Д.В., Фатхудинов Т.Х., Салихова Д.И., 2024

Creative Commons License
Эта статья доступна по лицензии Creative Commons Attribution-NonCommercial 4.0 International License.