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8Cellular Therapy and Transplantation (CTT). Vol. 12, No. 1, 2023 doi: 10.18620/ctt-1866-8836-2023-12-1-51-59 Submitted: 29 November 2022, accepted: 03 March 2023
Mesenchymal stem cells in complex treatment of urinary tract diseases: a literature review and our own experience
Nadezhda V. Orlova Alexander N. Muravyov Anna A. Gorelova Anna N. Remezova Tatiana I. Vinogradova Natalia M. Yudintceva 4, Yulia A. Nashchekina 4, Alexander I. Gorbunov Alexander A. Lebedev Andrei I. Gorelov 2, Petr K. Yablonsky 12
1 St. Petersburg Research Institute of Phtisiopulmonology, St.Petersburg, Russia
2 St. Petersburg State University, St. Petersburg, Russia
3 St. Petersburg Medico-Social Institute, St. Petersburg, Russia
4 Institute of Cytology RAS, St. Petersburg, Russia
Dr. Nadezhda V. Orlova, St. Petersburg Research Institute of Phone: +7 (953) 347-00-85
Phtisiopulmonology, Ligovsky 2-4, Ave, 191036, E-mail: [email protected]
St. Petersburg, Russia
Citation: Orlova NV, Muravyov AN, Gorelova AA, et al. Mesenchymal stem cells in complex treatment of urinary tract diseases: a literature review and our own experience. Cell Ther Transplant 2023; 12(1): 51-59.
Summary
Over recent years, the use of mesenchymal stem cells (MSCs) has been increasingly studied in complex therapy of various diseases, as well as in reconstruction of damaged organs and tissues. In particular, immunoreg-ulatory properties of MSCs are in scope, manifesting both by a direct effect on the target cells, and via signaling molecules and cytokines. This review is devoted to perspectives of using MSCs in urinary tract disorders, including the description of immunosuppressive mechanisms and the reasons for using this cell type in experimental and clinical practice. We also present our own experience of bladder reconstruction in animal model. We are currently studying the substitution cystoplasty using tissue-engineered constructs. The study is based on data from our previous experimental studies. We are testing poly-l-lactide/silk fibroin scaffold of different sizes seeded with MSCs using a rabbit bladder resection model, in order to find out what part of the bladder we could substitute. At this stage, there are positive results of 5- to 10-mL substitutional cystoplasty. According to multislice computed tomography of the abdominal cavity and small pelvis (native study and with intravesical administration of a radiopaque agent) 4 weeks post surgery, a bladder of physiological capacity (10-11 ml) is determined, without streaks of a contrast agent. Also, 4 weeks after the operation, the anastomosis zone is macroscopically consistent, the tissue-engineered structure is determined at the implantation site.
Conclusion
The unique immunomodulatory properties of mesen-chymal stem cells, combined with their multipotency, allow their usage in complex treatment of different clinical disorders. Moreover, both systemic use of MSCs and their application for tissue engineering constructs are feasible. The usage of such constructs consisting of a composite matrix and rabbit mesenchymal stem cells, proved to be effective for reconstruction of small bladder defects. Further advances in development of the multi-component grafts with allogeneic cells may improve the treatment outcomes in distinct disorders where autolo-gous biomaterial is not available.
Keywords
Mesenchymal stem cells, effects of mesenchymal stem cells, tissue-engineering construction, small bladder.
Introduction
Mesenchymal stem cells (MSCs) are currently of great interest in the field of regenerative medicine. Due to their multipotency, they are able to differentiate into various cell lines, including neural cells, adipocytes, smooth myocytes, urothelial and endothelial cells [1]. The secretome of MSCs contains various growth factors, cytokines and chemokines. However, a complete knowledge of their biological effects has not yet been achieved [2, 3]. Immunomodulatory and regenerative properties of MSCs are actively studied all over the world in the field of treatment of autoimmune diseases, transplantology, oncology, phthisiology, etc.
Initially, the MSCs were found in the bone marrow stroma. Later on, they were also revealed in other organs, such as the placenta, umbilical cord, liver, and adipose tissue [4]. Today, their presence in most organs and tissues has been proven. These cells are functionally a cell repair depot for maintaining cellular homeostasis and tissue regeneration. They are also known as "resting" stem cells.
The MSCs were firstly described in 1975 by Friedenstein et al. as fibroblast-like cells with the property of adhesion to plastic during cultivation [5]. These cells are called colony-forming fibroblast progenitors (CFU-f). Further numerous studies have confirmed their stem cell nature [5-7]. They were called mesenchymal stem cells, or mesenchymal progenitor cells, due to their ability to differentiate into various mesenchymal cell lines (osteoid, chondrogenic, adipogenic) [8,9]. The term mesenchymal stem cells is most often encountered in the literature. Regardless of the terminology used, all studies refer to adherent cells that, when cultured ex vivo, form colonies of spindle-shaped cells resembling fibroblasts in their morphology. Currently, MSCs isolated from bone marrow and adipose tissue are most commonly used due to their availability and opportunity of large-scale expansion of autologous MSCs from the patient.
MSCs main characteristics and mechanisms of action
Mesenchymal stem cells are multipotent and may differentiate to various cell lines. There is evidence that the cultured MSCs can undergo up to 19 doublings without losing their ability to proliferate and differentiate [10]. The ability of these cells to differentiate in adipogenic, osteogenic, and chondro-genic directions has been confirmed [11-13]. The ability of MSCs to differentiate in vitro into the cells with properties of smooth muscle, urothelial and endothelial cells has been also recently proven [14]. At the same time, some researchers doubt the existence of such multiple potencies [15].
MSCs secrete a wide range of bioactive macromolecules, both performing a regulatory function and promoting restoration of damaged tissue [2]. Mesenchymal stem cells exhibit pronounced immunosuppressive properties and render a regulatory effect on the immune system. Their antiprolifera-tive and anti-inflammatory effects are implemented by various mechanisms. E.g., MSCs are able to inhibit proliferation and function of major immune cell populations, including T cells, B cells, and NK cells, and also modulate activities
of dendritic cells and induce regulatory T cells, both in vivo and in vitro [16]. MSCs produce multiple cytokines, growth factors, and signaling molecules able to suppress the inflammatory response and stimulate neoangiogenesis. Numerous studies have shown that MSCs may suppress T-lymphocyte proliferation induced by alloantigens, mitogens, anti-CD3, anti-CD28 antibodies.
MSCs exert similar effects upon memory T-cells and naive T-cells [17], as well as on CD4+ and CD8+ T-cells [18]. Inhibition of T-cell proliferation is mediated both by intercellular interaction [19, 20], and by release of soluble factors, such as interferon-y (IFN-y) and interleukin-1^ (IL-1p) which are produced constantly or after cross interaction with target cells [21, 22]. According to a study by G. Ren et al., the immunosuppressive function of MSCs in mice is induced by IFN-y in co-operation with any of three other pro-inflammatory cytokines: TNFa, IL-1a, or IL-1p [23]. These combinations of cytokines induce high-level expression of several chemokines, primarily CXCL9, CXCL10 and CXCL11, which are ligands for the T-cell chemokine receptor CXCR3 and nitric oxide synthase in MSCs. Via the chemokine effects, T-cells migrate in the close proximity to MSCs, where a cascade of T-lymphocyte apoptosis is triggered under the action of nitric oxide [24]. According to other data, MSCs produce indolaminepyrrole-2,3-dioxygenase in the presence of IFN-y, thus leading to catabolism of tryptophan, an essential amino acid, which in turn suppresses proliferation of effector cells, including T-lymphocytes [18].
As for the effect of MSCs on B cells, one should note that they inhibit the proliferation of B cells activated by antiimmunoglobulin antibodies, anti-CD40L antibodies, and cytokines (IL-2 and IL-4). In addition, MSCs impair the production of antibodies by B-cells and secretion of CXCR4, CXCR5, and CCR7 chemokine receptors which are responsible for chem-otaxis to CXCL12 and CXCL13. However, MSCs do not affect the expression of B-cell costimulatory molecules and production of cytokines [25]. The main mechanism of B-cell suppression is explained by physical contact between B cells and MSCs, as well as soluble factors released by the latters, thus leading to blocking of B cell proliferation in the G0/G1 phase of cell cycle without apoptosis [25, 26], in contrast to the case with T cells.
Some studies have shown that MSCs suppress NK cell proliferation and IFN-y production, presumably due to IL-2 or IL-15, and also partially inhibit proliferation of activated NK cells [27]. Factors such as transforming growth factor (TGF-^1) and prostaglandin E-2 (PGE-2) play an important role in MSC-mediated suppression of NK cell proliferation [20]. However, Spaggiari et al. have noted that the IL-2-ac-tivated NK-cells effectively lysed autologous and allogeneic MSCs. The main receptors for NK cell activation are NKp30, NKG2D, and DNAM-1 which are involved in NK-cell-medi-ated cytotoxicity against MSCs, which is associated with expression of ligands for ULBPs, PVR, and Nectin-2 receptors on the surface of mesenchymal cells [28].
MSCs impair differentiation of monocytes and CD34+ he-matopoietic stem cells to dendritic cells (DCs) by inhibiting the response of monocytes to maturation signals, decreasing expression of some molecules, e.g., CD40, CD86, and CD83,
and interfering with ability of the latter to stimulate naive T cell proliferation and secretion of IL-12 [29-33]. After interaction with DCs of myeloid origin, MSCs produce TNFa at small amounts, while plasma DCs produce increased amounts of IL-10 and TNFa, which play an important role in maturation, migration, and presentation of DC antigens. The mechanism of MSC-induced inhibition of DC maturation, differentiation, and function is mediated by prostaglandin E2 released upon contact between the cells [34].
Thus, it can be concluded that MSCs exert a pronounced immunosuppressive effect. These cells acquire this property when stimulated with combinations of IFN-y and TNFa, IL-1a or IL-1^. It has also been confirmed that there is species-specific variability in the mechanisms of MSC-mediated immunosuppression: (1) the effects produced by cytokine-induced mouse MSCs occurs via NO [23], whereas immunosuppression by cytokine-exposed human MSCs depends on IDO effects [18]. Moreover, both mouse and human MSCs, if stimulated by inflammatory cytokines, secrete leukocyte chemokines that serve to attract immune cells in close proximity to MSCs, where NO or IDO is most active.
Therefore, immunosuppression by MSCs stimulated by inflammatory cytokines occurs through the concerted action of chemokines and NO or IDO. The ability of MSCs for immunosuppression allows usage of these cells in order to suppress reactivity of donor T-lymphocytes to the histocompatibility antigens of recipient, and prevent the development of graft-versus-host disease (GVHD) following allogeneic transplantation.
Several works dealing with MSC migration to the damage or inflammation sites have demonstrated that this phenomenon is mediated by chemotactic factors produced by immune cells. Human MSCs are shown to react by chemotaxis to several factors, including platelet growth factor (PDGF), VEGF, IGF-1, IL-8, bone morphogenetic protein (BMP)-4 and BMP-7 [35], as well as TNFa, which is a key regulator of the NF-kB pathway. The NF-kB pathway plays an important role in regulation of genes that affect cell migration, proliferation, differentiation, and apoptosis, as well as inflammation [36]. Attraction of MSCs to the damaged area results in rapid restoration of damaged tissues.
All of the above mechanisms of MSC action on surrounding tissues underlie their therapeutic effects in the treatment of various pathological conditions, affecting different components of the immune system and regulating the release of signaling molecules. A clear understanding of the relationship between signaling molecules and MSCs in the microenvironment is required for their use in the treatment of specific clinical disorders.
Mesenchymal stem cells in treatment of kidney and urinary diseases
A number of studies are devoted to investigation of adjunctive therapy for renal diseases using MSCs. Kidney is the most complex organ of the genitourinary system in terms of regeneration, due to its intricate architecture and cell heterogeneity, thus making the development of cell therapy for renal failure a difficult task. The regenerative potential of MSCs is often studied under the conditions of acute kidney injury
or chronic kidney disease, when the amount of functioning renal parenchyma is insufficient for the full-scale functioning of the organ.
According to some data, bone marrow-derived MSCs are able to differentiate and eventually regenerate several cell lines, including glomerular endothelial cells by promoting angiogenesis in the areas of significant damage to the renal parenchyma [37]. Additional experiments in a murine model of renal ischemia-reperfusion showed that the majority of regenerated cells arise from renal tubular epithelial cells derived from recipient cells [38].
MSCs regulate the repair process by differentiating into several types of stromal and/or damaged cell types, as well as by providing a microenvironment through interaction with many types of tissue and immune cells, such as fibroblasts, endothelial and epithelial cells, macrophages, neutrophils, and lymphocytes. This interaction is believed to be critical for creating a microenvironment for tissue regeneration and wound healing [23].
It is assumed that MSCs from the nearby environment or bone marrow migrate to the areas of damaged tissue, and release a number of growth factors, such as epidermal growth factor (EGF), fibroblast growth factor (FGF), PDGF, TGF^, vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), angiopoietin-1, and stromal cell-derived factor-1 (SDF-1). All of them can influence the development of fibroblasts and endothelial cells [3]. This is a very important property of MSCs, which can be used to enhance the recovery of all types of damage in the body.
Several animal models have been used to determine the renoprotective abilities of systemically administered bone marrow MSCs in case of kidney injury [37, 40]. In a murine model of cisplatin-induced kidney injury, the injected MSCs differentiated into tubular epithelial cells [41], increased the rate of renal tubular proliferation, and significantly decreased serum urea levels. According to Togel et al., in a rat model of ischemia-reperfusion, the fluorescently labeled MSCs were injected 24 hours later. After euthanasia, these cells were visualized in the area of glomerular basement membranes. As a result, several renoprotective effects were obtained after MSC administration, including restoration of kidney function, high proliferation levels, and low apoptotic rates. However, within 3 days after administration, MSCs did not differentiate into a tubular or endothelial cell phenotype. Therefore, the authors concluded that the beneficial effects of MSCs are primarily mediated by complex paracrine mechanisms of interaction with renal parenchyma cells, rather than their differentiation into target cells [42].
In a work by Morigi et al., MSCs obtained from umbilical cord blood were injected into mice with cisplatin-induced kidney injury. Administration of MSCs led to the production of growth factors and inhibition of inflammatory mediators (IL-1p and TNF-a) [41]. There are also some data suggesting a positive effect of bone marrow MSCs in various immune-mediated disorders [43, 44].
Kirpatovskiy et al. [45] performed a study on rats with E.coli-induced pyelonephritis. After the induction of chronic pyelonephritis, the authors observed development of an
infectious and inflammatory process in the kidneys, as well as deterioration of renal functions. The injection of MSCs led to short-term decrease in the inflammatory process in kidneys, i.e., reduction of leukocyturia, proteinuria, bacte-riuria in 20% of animals. Upon assessment of renal functional state, a persistent improvement in the main laboratory indices was registered. The markers of inflammation and functional disorders of kidneys were preserved in animals that did not receive the treatment. Assessment of humoral immunity showed a decreased level of immunoglobulin G (IgG) and C3 component of complement in the blood of rats with chronic pyelonephritis. Hence, it turned out that MSCs reduce the severity of inflammatory response and alleviate the negative effects of long-term inflammation. Moreover, the indices of humoral immunity did also undergo changes. Normalization of impaired immunological parameters was achieved, which in turn contributes to better morphological preservation of nephrons in certain parts of the organ. All the above findings point to the immunomodulatory effects of MSCs.
In recent years, more and more studies focus on the role of MSCs in the regulation of tolerance to allograft rejection and graft-versus-host disease (GVHD) due to their immuno-modulatory effects, such as suppressed reactivity of the donor T-cells to histocompatibility antigens of normal tissues in the recipient [46]. Immunomodulatory effects of MSCs were evaluated in a clinical study of eight patients with steroid-resistant GVHD. As a result, 6 out of 8 patients exhibited resolution of the disease, along with significantly increased survival rate compared with patients who did not receive MSCs [47]. In a subsequent phase II multicentre clinical trial of MSCs therapy in steroid-resistant acute GVHD, 55 patients were treated with MSCs [48]. A complete response was achieved in 30 patients, and another 9 patients showed clinical improvement. No side effects were observed during or immediately after MSC infusion.
Sudres et al. found that MSCs failed to prevent GVHD in mice, due to MSC rejection [49]. However, Shi et al. have reported that MSCs can prolong the survival rate in mu-rine model of GVHD [50]. There was only one difference between the two studies, i.e., the timing of MSC administration. In the first experiment, the MSCs were injected 1015 min before GVHD induction, while in second study, on days +3 and +7 after bone marrow transplantation. Probably, the timing of MSC infusion is important for the therapeutic effect. Another study from 2008 showed that pretreatment with TNFa before transplantation can increase the efficiency of MSC administration [23].
Based on the fact, that the immunosuppressive ability of MSCs should be induced by inflammatory cytokines, one may assume that infusion of MSCs at the peak of inflammation may improve the therapeutic effect. In a randomized open clinical trial in patients undergoing kidney transplantation, the use of induction therapy with autologous MSCs resulted in reduced incidence of acute graft rejection and lower risk of opportunistic infection. Also, a higher rate of renal function recovery during the first month after surgery was detected compared with standard induction therapy with antibodies against the IL-2 receptor [51].
A group of workers from our institution studied the distribution of labeled MSCs in various tissues and organs using a rabbit model of kidney tuberculosis. Within 48 hours after the injection, the labeled MSCs were accumulated in lungs, spleen, liver tissues, and paratracheal lymph nodes, with a decrease in their concentration by the 7th day. At the same time, concentration of MSCs in the kidneys affected by tuberculosis did not decrease during the entire observation period. Thus, a mechanism of in vivo MSC migration was suggested under the conditions of tuberculosis infection [52, 53].
Moreover, MSCs may be used as a component of tissue-engineered grafts for reconstruction of various urological structures, including the bladder [54-58]. Our research group has own positive experimental experience with MSCs applications in bladder and urethral plastic surgery [59-61]. E.g., in a recent study, 15 rabbits underwent partial bladder resection with implantation of scaffolds containing, e.g., smooth muscle cells, urothelium, fibroblasts, and mesenchymal stem cells, as well as a cell-free matrix. In the group of animals that received a scaffold with labeled mesenchymal stem cells, no signs of implant rejection were observed in five cases out of six. 2.5 months after the surgery, the bladder capacity was comparable to the preoperative one. At the site of implantation, the area of the newly formed bladder wall with signs of vascularization was evident, and histological examination revealed the initial stages of repair and angiogenesis. Confocal microscopy of cryosections at the site of implantation identified labeled cells involved in formation of urothelium-like structure. In all cases of implantation with a cell-free matrix, or scaffolds containing smooth muscle cells, urothelium and fibroblasts, the implant was rejected with varying degrees of inflammatory response and decreased bladder capacity.
We are currently testing substitution cystoplasty using tissue-engineered constructions. The study is based on results of our previous experimental studies [55]. We use different sizes of poly-l-lactide/silk fibroin scaffold seeded with MSCs in a rabbit model to understand what part of the bladder could be substituted.
Materials and methods
The matrix was composed of poly-L,L-lactide base, reinforced with silk fibroin. Prepared scaffolds were seeded with cells, employing cell line Rb MSC obtained from the shared research facility "Vertebrate cell culture collection" of the Institute of Cytology of the Russian Academy of Sciences (Saint Petersburg, Russia).
6 intact animals underwent filling cystometry using saline at room temperature: infusion through a urethral urodynamic catheter at a rate of 5 mL/min with synchronous recording of abdominal pressure through a rectal sensor. The maximum cystometric capacity was 11.2±0.97 mL; this volume showed a contraction of the detrusor with the urine flow past the catheter. Intravesical pressure at the beginning of the urine flow - 26.03±3.2 cm of water, the maximum value is 38.26±3.48 cm of water.
In the same 6 animals, the anesthetic bladder capacity was measured by infusion through a urethral catheter at a pressure of 20 cm H2O. The anesthetic capacity was
23.83±0.71 mL, and the stoppage of the solution flow was recorded on this volume.
Cystoplasty was performed with a tissue-engineered reservoir in 18 laboratory animals after preliminary resection of parts of the bladder corresponding in volume (Fig. 1). In the moment, the bladder volume has been replaced by 5 ml (n=9) and 10 ml (n=9).
All studies were carried out in accordance with the ethical principles of laboratory animals curation "European Convention for the Protection of Vertebral Animals Used for Experimental and Other Scientific Purposes. CETS No. 123" and the Rules of Laboratory Practice (Order of the Ministry of Health and Social Development of the Russian Federation, August 23, 2010 No708n "On Approval of the Rules of Laboratory Practice"). The study was approved by the Independent Ethics Committee at the Federal State Budgetary Institution "SPb NIIF" of the Ministry of Health of Russia (extract from protocol 91.3 dated 21.09.2022).
Results
At this stage, there are positive results of 5- to 10-mL substitutional cystoplasty.
According to multislice computed tomography of the abdominal cavity and small pelvis (native study and with intravesical administration of a radiopaque substance) 4 weeks after surgery, the bladder of physiological capacity (10-11 mL) is determined. The implanted structure is visualized as a hyperintense signal in the region of implantaton (Fig. 2). There is no leakage of contrast agent.
Moreover, we derived from the experiment 6 animals that underwent replacement of part of the bladder with a volume of 5 mL (n=3) and 10 mL (n=3). The observation period consisted 4 weeks. Macroscopically, the anastomosis area is well-founded, the tissue-engineered structure is determined at the implantation site. The preparations were sent for histo-logical examination and confocal microscopy of sections in the implantation zone.
A
B
C
Figure 1. The stages of surgical intervention: a) view of the scaffold; b) view of the bladder after resection of K volume (10 ml); c) view of the implanted tissue-engineered reservoir to replace the volume of 10 ml
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A
B
Figure 2. Results of the rabbit bladder replacement at a volume of 5 ml (4 weeks post surgery). Multislice computed tomography of the abdominal cavity and small pelvis: a) native study. b) with intravesical administration of a radiopaque substance
The research group plans to continue monitoring animals that have already been operated on, up to 12 weeks. As well as performing replacement cystoplasty with a tissue-engineered reservoir in 18 laboratory animals with replacement of the bladder volume by 15 mL (n=9) and 20 mL (n=9). It is also necessary to evaluate the possibility and feasibility of replacing such volumes of the bladder, taking into account the data on the physiological capacity of the bladder in a volume of 11.2 ± 0.97 mL obtained earlier by filling cystometry.
Conclusion
The unique immunomodulatory properties of mesenchy-mal stem cells combined with their multipotency, allow their usage in complex treatment of different clinical disorders. Moreover, both systemic use of MSCs and the use of tissue engineering constructs are possible. The use of such construct, consisting of a composite matrix and rabbit mesenchymal stem cells, proved to be effective for the reconstruction of small bladder defects. Further advances in development of the multicomponent grafts with allogeneic cells may improve the treatment outcomes in distinct disorders where the autologous material is not available.
Acknowledgements
This study is being carried out on the basis of the SPbNIIF at the expense of the Russian Science Foundation grant No. 22-25-20167, https://rscf.ru/project/22-25-20167/ and the St. Petersburg Science Foundation grant in accordance with an agreement dated April 14, 2022 No. 20/2022.
Conflict of interest
The authors state that there is no conflict of interest. The authors bear full responsibility for providing the final version of the manuscript to the press. All authors took part in the development of the concept of the article and the writing of the manuscript. The final version of the manuscript was approved by all authors.
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Мезенхимные стволовые клетки в комплексном лечении заболеваний мочевыводящих путей: обзор литературы и собственный опыт
Надежда В. Орлова Александр Н. Муравьев 1'3, Анна А. Горелова 1'2, Анна Н. Ремезова Татьяна И. Виноградова Наталья М. Юдинцева 4, Юлия А. Нащекина 4, Александр И. Горбунов 1, Александр А. Лебедев 1, Андрей И. Горелов 2, Петр К. Яблонский 1,2
1 Санкт-Петербургский научно-исследовательский институт фтизиопульмонологии, Санкт-Петербург, Россия
2 Санкт-Петербургский государственный университет, Санкт-Петербург, Россия
3 Санкт-Петербургский медико-социальный институт, Санкт-Петербург, Россия
4 Институт цитологии Российской академии наук, Санкт-Петербург, Россия
Резюме
В последние годы все более широко исследуется применение мезенхимных стволовых клеток (МСК) в комплексной терапии различных заболеваний, а также в реконструкции поврежденных органов и тканей. Изучаются иммунорегулирующие свойства МСК, проявляющиеся как прямым воздействием на клетки-мишени, так и с помощью сигнальных молекул и цитокинов. Данный обзор посвящен возможностям применения МСК при урологической патологии, в том числе описанию механизмов имму-носупрессивного действия и перспективам использования этого типа клеток в экспериментальной и клинической практике. Представлен также собственный опыт реконструкции мочевого пузыря на животной модели. В настоящее время мы изучаем заместительную цистопластику с использованием тканеинженерных конструкций. Исследование основано на данных наших предыдущих экспериментальных исследований. В качестве скаффолдов мы используем матрицы из поли-1-лактида/фиброина шелка разных размеров, засеянные аллогенными МСК, на модели резекции мочевого пузыря кролика, чтобы понять, какую часть мочевого пузыря возможно заменить. На данном этапе были позитивные результаты от заместительной цистопластики (5-10 мл). По данным МСКТ органов брюшной полости и малого таза (нативное исследование и с внутрипузырным введением рентгенконтрастного вещества) через 4 недели после оперативного вмешательства определяется мочевой пузырь физиологической емкости (10-11 мл), без затеков контрастного вещества. Также через 4 недели после операции макроскопически зона анастомоза состоятельна, тканеинженерная конструкция определяется в месте имплантации.
Заключение
Уникальные иммуномодулирующие свойства мезен-химных стволовых клеток в сочетании с их мульти-потентностью позволяют применять их в комлекс-ном лечении обширного спектра патологий. Причем возможно как системное применение МСК, так и использование тканеинженерных конструкций. Применение подобной конструкции, состоящей из композитной матрицы и мезенхимных стволовых клеток кролика оказалось эффективным для реконструкции небольших дефектов мочевого пузыря. Дальнейшая разработка методик создания многокомпонентного трансплантата с использованием ал-логенных клеток может способствовать улучшению результатов лечения таких патологий, при которых получение аутологичного материала не представляется возможным.
Ключевые слова
Мезенхимные стволовые клетки, эффекты мезен-химных стволовых клеток, тканеинженерная конструкция, малый мочевой пузырь.
