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multipotent stromal cells stimulate liver regeneration by influencing the macrophage polarization in rat

World Journal of Hepatology 2018年第2期10卷 287-296页

作者： Andrey Elchaninov Timur Fatkhudinov Natalia Usman Irina Arutyunyan Andrey Makarov Anastasia Lokhonina Irina Eremina Viktor Surovtsev Dmitry Goldshtein Galina Bolshakova Valeria Glinkina Gennady Sukhikh National Medical Research Center for Obstetrics Gynecology and Perinatology named after Academician V.I.Kulakov of Ministry of Healthcare of Russian FederationMoscow 117997Russia Peoples Friendship University of Russia(RUDN University) Moscow 117198Russia Scientific Research Institute of Human Morphology Moscow 117418Russia Pirogov Russian National Research Medical University Ministry of Healthcare of the Russian FederationMoscow 117997Russia Research Center of Medical Genetics Moscow 115478Russia

AIM To investigate the influence of the umbilical cordderived multipotent stromal cells(MSCs) on recovery of the liver after the subtotal resection, that is, removal of 80% of the organ mass, a renowned model of the small-for-size liver remnant syndrome. METHODS The MSCs were obtained from the intervascular tissue of umbilical cords, dissected from rat fetuses, by the explant culture technique. The vital labeling of MSCs with РКН26 was carried out on the 3 rd passage. The subtotal resection was performed on male Sprague-Dawley rats. The experimental group animals received a transplant 106 MSCs infused into the spleen. Hepatocyte proliferation was assessed by counting of either mitotic figures or Ki67-positive cells in microscopic images. MSC differentiation was assessed with antibodies to hepatocyte-specific marker cytokeratin 18(CK18), cholangiocyte-specific protein CK19, smooth muscle cell-specific protein α-SMA, the endothelial cell marker CD31, or the active fibroblast marker FAPα. Total macrophages of the liver were selectively stained in cryosections incubated with antiCD68 antibodies(1:100, Abcam), while the M2 a and M2 c macrophage populations were selectively stained with anti-CD206 antibodies. Expression of interleukin and growth factor genes was evaluated with PCR-RT.RESULTS Intrasplenic allogeneic transplantation of the umbilical cord-derived multipotent stromal cells stimulates reparative processes within the residual liver tissue after subtotal resection(removal of 80% of the organ mass), as indicated by increased rates of hepatocyte proliferation and accelerated organ mass recovery. These effects may result from paracrine influence of the transplanted cells on the resident macrophage population of the liver. The transplantation favors polarization of macrophages to M2 phenotype(the M2-polarized macrophages specifically express CD206; they are known to suppress inflammation and support tissue repair). No differentiation of the transplanted cells into any of the liver cell types have been observed in

关键词： Liver Regeneration multipotent stromal cells Macrophages

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Insight into generation of induced mesenchymal stem cells from induced pluripotent cells

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World Journal of Stem Cells 2022年第1期14卷 142-145页

作者： Mahmood S Choudhery Ruhma Mahmood Department of Biomedical Sciences King Edward Medical UniversityLahore 54000PunjabPakistan Department of Genetics and Molecular Biology University of Health SciencesLahore 54600PunjabPakistan Stem Cells Laboratory Allama Iqbal Medical CollegeLahore 54000PunjabPakistan

Mesenchymal stem cells(MSCs)have the potential for use in cell-based regenerative therapies.Currently,hundreds of clinical trials are using MSCs for the treatment of various diseases.However,MSCs are low in number in adult tissues;they show heterogeneity depending upon the cell source and exhibit limited proliferative potential and early senescence in in vitro cultures.These factors negatively impact the regenerative potential of MSCs and therefore restrict their use for clinical applications.As a result,novel methods to generate induced MSCs(iMSCs)from induced pluripotent stem cells have been explored.The development and optimization of protocols for generation of iMSCs from induced pluripotent stem cells is necessary to evaluate their regenerative potential in vivo and in vitro.In addition,it is important to compare iMSCs with primary MSCs(isolated from adult tissues)in terms of their safety and efficacy.Careful investigation of the properties of iMSCs in vitro and their long term behavior in animals is important for their translation from bench to bedside.

关键词： Induced mesenchymal stem cells Induced pluripotent stem cells Regenerative potential Pluripotent multipotent Clinical studies

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multipotent pancreas progenitors: Inconclusive but pivotal topic

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World Journal of Stem Cells 2015年第11期7卷 1251-1261页

作者： Fang-Xu Jiang Grant Morahan Islet Cell Development Program Harry Perkins Institute of Medical Research Centre for Medical Research the University of Western Australia Centre for Diabetes Research Harry Perkins Institute of Medical Research

The establishment of multipotent pancreas progenitors(MPP) should have a significant impact not only on the ontology of the pancreas, but also for the translational research of glucose-responding endocrine b-cells. Deficiency of the latter may lead to the pandemic type 1 or type 2 diabetes mellitus, a metabolic disorder. An ideal treatment of which would potentially be the replacement of destroyed or failed b-cells, by restoring function of endogenous pancreatic endocrine cells or by transplantation of donor islets or in vitro generated insulin-secreting cells. Thus, considerable research efforts have been devoted to identify MPP candidates in the preand post-natal pancreas for the endogenous neogenesis or regeneration of endocrine insulin-secreting cells. In order to advance this inconclusive but critical field, we here review the emerging concepts, recent literature and newest developments of potential MPP and propose measures that would assist its forward progression.

关键词： multipotent pancreas progenitors Regeneration Self-renewal Clonogenesis Differentiation

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Long non-coding RNA: The functional regulator of mesenchymal stem cells

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World Journal of Stem Cells 2019年第3期11卷 167-179页

作者： Zhong-Yu Xie Peng Wang Yan-Feng Wu Hui-Yong Shen Department of Orthopedics The Eighth Affiliated Hospital Sun Yat-sen University Center for Biotherapy Sun Yat-sen Memorial Hospital Sun Yat-sen University

Mesenchymal stem cells(MSCs) are a subset of multipotent stroma cells residing in various tissues of the body. Apart from supporting the hematopoietic stem cell niche, MSCs possess strong immunoregulatory ability and multiple differentiation potentials. These powerful capacities allow the extensive application of MSCs in clinical practice as an effective treatment for diseases.Therefore, illuminating the functional mechanism of MSCs will help to improve their curative effect and promote their clinical use. Long noncoding RNA(LncRNA) is a novel class of noncoding RNA longer than 200 nt. Recently,multiple studies have demonstrated that LncRNA is widely involved in growth and development through controlling the fate of cells, including MSCs. In this review, we highlight the role of LncRNA in regulating the functions of MSCs and discuss their participation in the pathogenesis of diseases and clinical use in diagnosis and treatment.

关键词： Mesenchymal stem cells Long non-coding RNA Regulator multipotent stroma cells

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Comparison of phenotypic markers and neural differentiation potential of multipotent adult progenitor cells and mesenchymal stem cells

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World Journal of Stem Cells 2013年第2期5卷 53-60页

作者： Saurabh Pratap Singh Naresh Kumar Tripathy Soniya Nityanand Stem Cell Research Facility Department of Hematology Sanjay Gandhi Post-Graduate Institute of Medical SciencesLucknow 226014 India

AIM: To compare the phenotypic and neural differentiation potential of human bone marrow derived multipotent adult progenitor cells (MAPC) and mesenchymal stem cells (MSC). METHODS: Cultures of MAPC and MSC were established in parallel from same samples of human bone marrow (n = 5). Both stem cell types were evaluated for expression of pluripotency markers including Oct-4 and Nanog by immunocytochemistry and reversetranscription polymerase chain reaction (RT-PCR) and expression of standard mesenchymal markers including CD14, CD34, CD44, CD45, CD73, CD90, CD105 andhuman leukocyte antigen (HLA)-ABC by flow cytometry. After treatment with neural induction medium both MAPC and MSC were evaluated for expression of neural proteins [neuronal filament-200 (NF-200) and glial fibrillar acidic protein (GFAP)] by immunocytochemistry and Western blotting and neural genes [NF-200, GFAP, Tau, microtubule-associated protein (MAP)-1B, MAP-2, neuron-specific enolase (NSE) and oligodendrocyte-1 (Olig-1)] by quantitative real-time-PCR. RESULTS: MAPC had small trigonal shaped while MSC had elongated spindle-shaped morphology. The MAPC expressed Oct-4 and Nanog both at gene and protein levels, whereas MSC were negative for these pluripotent markers. MAPC were negative for HLA-ABC while MSC had high expression of HLA-ABC. In addition, MAPC as compared to MSC had significantly lower expression of CD44 (36.56% ± 1.92% vs 98.23% ± 0.51%), CD73 (15.11% ± 2.24% vs 98.53% ± 2.22%) and CD105 (13.81% ± 3.82%vs 95.12% ± 5.65%) (P < 0.001, for all) MAPC cultures compared to MSC cultures treated with neural induction medium had significantly higher fold change expression of NF-200 (0.64), GFAP (0.52), Tau (0.59), MAP-2 (0.72), Olig-1 (0.18) and NSE (0.29) proteins (P < 0.01 for Olig-1 and P < 0.001 for rest) as well as higher fold change expression of genes of NF-200 (1.34),GFAP (1.12),Tau (1.08),MAP-1B (0.92), MAP-2 (1.14) andNSE (0.4) (P < 0.001 for all). CONCLUSION: MAPC can be differentially characterized from MSC as Oct-4 and Nanog positive

关键词： Bone marrow Human multipotent adult progenitor cells Human mesenchymal Stem cells Phenotypic markers Neural differentiation

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Neural regeneration by regionally induced stem cells within poststroke brains: Novel therapy perspectives for stroke patients

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World Journal of Stem Cells 2019年第8期11卷 452-463页

作者： Takayuki Nakagomi Toshinori Takagi Mikiya Beppu Shinichi Yoshimura Tomohiro Matsuyama Institute for Advanced Medical Sciences Hyogo College of Medicine Nishinomiya Hyogo 663-8501 Japan Department of Therapeutic Progress in Brain Diseases Hyogo College of Medicine Nishinomiya Hyogo 663-8501 Japan Department of Neurosurgery Hyogo College of Medicine Nishinomiya Hyogo 663-8501 Japan

Ischemic stroke is a critical disease which causes serious neurological functional loss such as paresis. Hope for novel therapies is based on the increasing evidence of the presence of stem cell populations in the central nervous system (CNS) and the development of stem-cell-based therapies for stroke patients. Although mesenchymal stem cells (MSCs) represented initially a promising cell source, only a few transplanted MSCs were present near the injured areas of the CNS. Thus, regional stem cells that are present and/or induced in the CNS may be ideal when considering a treatment following ischemic stroke. In this context, we have recently showed that injury/ischemia-induced neural stem/progenitor cells (iNSPCs) and injury/ischemia-induced multipotent stem cells (iSCs) are present within post-stroke human brains and post-stroke mouse brains. This indicates that iNSPCs/iSCs could be developed for clinical applications treating patients with stroke. The present study introduces the traits of mouse and human iNSPCs, with a focus on the future perspective for CNS regenerative therapies using novel iNSPCs/iSCs.

关键词： Ischemic stroke Stroke patients Central nervous system Neural stem/progenitor cells multipotent stem cells Stem-cell-based therapies

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A study on the activity of dermal multipotent stem cells in initiation of wound repair

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Journal of Biomedical Science and Engineering 2013年第2期6卷 109-115页

作者： Jifu Qu Tianmin Cheng Yongping Su Chunmeng Shi Wei Sun State Key Laboratory of Trauma Burn and Combined Injury and Institute of Combined Injuries of Chinese PLA Academy of Preventive Medicine Third Military Medical University Chongqing China Trauma Center Department of Emergency Medicine Southwest Hospital Third Military Medical University Chongqing China

Background: Wound healing is a process of cell-cell interaction and cell-extracellular matrix interaction. Dermal multipotent stem cells (dMSCs) have the abilities to promote survival and wound healing, but the potential function of dMSCs in wound healing, particularly in the initiation of wound repair, has not been fully understood. Methods: dMSCs and fibroblasts were isolated from neonatal rat dermis and were further purified and expanded. The cell cycles were determined with flow cytometry, while the radiosensitivity was measured by MTT assay. Rats were wounded with a 7-cm incision on the back skin and the wound fluids were collected by inserting two pieces of sterile polyvinyl alcohol sponge (1 cmin diameter and0.4 cmin thickness) subcutaneously into the dorsum of each rat through the midline of incision on the 1st, 2nd, 3rd and 4th day after incision. The effects of wound fluids on the proliferation of dMSCs and fibroblasts were measured with MTT assays. dMSC’s abilities of adhesion and attachment and its migration in response to wound fluids collected on the 1st day after incision were explored by measuring the percentage of floating cells and the cells migrated into wounding area in vitro, respectively. Results: The isolated dMSCs were morphologically homogenous and highly proliferative. Most of the cultured dMSCs were quiescent with few apoptotic cells. Compared with fibroblasts, dMSCs were more sensitive to radiation and more proliferative in response to wound fluids, especially to the wound fluids collected on the 1st day after wounding. Moreover, their abilities to attach, adhere and migrate were significantly enhanced with the early-phase wound fluids. Conclusions: As primitive stem cells, dMSCs are very responsive to wound fluids, which suggests dMSCs’ important role in wound healing, especially in initiating wound repair.

关键词： Dermal multipotent Stem Cells Initiation of Wound Repair Wound Healing Wound Fluids

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Mini-review:Plasticity of human menstrual blood stem cells derived from the endometrium

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2011年第5期12卷 372-380页

作者： Jian LIN Dennis XIANG Jin-long ZHANG Julie ALLICKSON Charlie XIANG State Key Laboratory for Diagnosis and Treatment of Infectious Diseases the First Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310003 China Department of Chemical and Biomolecular Engineering Johns Hopkins University Baltimore MD 21218 USA Infectious Disease Unit Zhejiang Armed Police Hospital Jiaxing 314000 China Cryo-Cell International Inc. Oldsmar FL 34677 USA S-Evans Biosciences Hangzhou 311121 China J. Craig Venter Institute Rockville MD 20850 USA

Stem cells can be obtained from women's menstrual blood derived from the endometrium.The cells display stem cell markers such as Oct-4,SSEA-4,Nanog,and c-kit(CD117),and have the potent ability to differentiate into various cell types,including the heart,nerve,bone,cartilage,and fat.There has been no evidence of teratoma,ectopic formation,or any immune response after transplantation into an animal model.These cells quickly regenerate after menstruation and secrete many growth factors to display recurrent angiogenesis.The plasticity and safety of the acquired cells have been demonstrated in many studies.Menstrual blood-derived stem cells(MenSCs) provide an alternative source of adult stem cells for research and application in regenerative medicine.Here we summarize the multipotent properties and the plasticities of MenSCs and other endometrial stem cells from recent studies conducted both in vitro and in vivo.

关键词： Menstrual blood-derived stem cells(MenSCs) Endometrium multipotent Plasticity

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Hierarchy of mesenchymal stem cells: Comparison of multipotentmesenchymal stromal cells with fibroblast colony forming units

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Journal of Biomedical Science and Engineering 2013年第8期6卷 66-73页

作者： Irina N. Shipounova Natalia A. Petinati Alexey E. Bigildeev Natalia V. Sats Nina J. Drize Larisa A. Kuzmina Elena N. Parovichnikova Valery G. Savchenko Bone Marrow Transplantation Department FGBI National Hematological Scientific Center Moscow Russia Laboratory for Physiology of Hematopoiesis FGBI National Hematological Scientific Center Moscow Russia

The organization of the compartment of mesenchymal stem cells is still obscure. Two types of human stromal precursor cells are known. Both of them are analyzed in in vitro system: mesenchymal multipotent stromal cells (MMSC) and fibroblast colony forming units (CFU-F). The aim of this study was to compare the main characteristics of MMSC and CFU-F derived from the bone marrow of 24 healthy donors. Growth and differentiation parameters, as well as relative expression levels of different genes were analyzed in MMSC and CFU-F. MMSC were cultivated for 5 passages. CFU-F concentration was determined for each bone marrow sample. The data obtained demonstrated the heterogeneity and hierarchical organization of both studied populations of stromal precursor cells-MMSC and CFU-F. These two types of stromal precursor cells turned to be different in most parameters studied. Altogether MMSC seemed to be more immature cells than CFU-F and took up the higher position in hierarchical tree of mesenchymal stem cells. The rate of differentiation and proliferative potential decreased with the donor’s age in both populations MMSC and CFU-F.

关键词： Mesenchymal multipotent Stromal Cells (MMSC) Fibroblast Colony Forming Units (CFU-F) Real-Time Polymerase Chain Reaction Gene Expression Level Aging

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New insights for pelvic radiation disease treatment:multipotent stromal cell is a promise mainstay treatment for the restoration of abdominopelvic severe chronic damages induced by radiotherapy

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World Journal of Stem Cells 2013年第4期5卷 106-111页

作者： Alain Chapel Sabine Francois Marc Benderitter Luc Douay Jan Voswinkel Radiological Protection and Human Health Division Institute of Radiological Protection and Nuclear Safety PRP-HOM/SRBE/Laboratory of Radiopathology and Experimental Therapies Department of Hematology Saint Antoine Hospital APHP and UPMC University

Radiotherapy may induce irreversible damage on healthy tissues surrounding the tumor. It has been reported that the majority of patients receiving pelvic radiation therapy show early or late tissue reactions of graded severity as radiotherapy affects not only the targeted tumor cells but also the surrounding healthy tissues. The late adverse effects of pelvic radiotherapy concern 5% to 10% of them, which could be life threatening. However, a clear medical consensus concerning the clinical management of such healthy tissue sequelae does not exist. Although no pharmacologic interventions have yet been proven to efficiently mitigate radiotherapy severe side effects, few preclinical researches show the potential of combined and sequential pharmacological treatments to prevent the onset of tissue damage. Our group has demonstrated in preclinical animal models that systemic mesenchymal stromal cell(MSC) injection is a promising approach for the medical management of gastrointestinal disorder after irradiation. We have shown that MSCs migrate to damaged tissues and restore gut functions after irradiation.We carefully studied side effects of stem cell injection for further application in patients. We have shown that clinical status of four patients suffering from severe pelvic side effects resulting from an over-dosage was improved following MSC injection in a compationnal situation.

关键词： Cell therapy Radiotherapy Irradiation Stem cells multipotent stromal cells Mesenchymal stem cells Clinical trial

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