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Castilho RM, Castilho LS, Palomares BH, Squarize CH. Determinants of Chromatin Organization in Aging and Cancer-Emerging Opportunities for Epigenetic Therapies and AI Technology. Genes (Basel) 2024; 15:710. [PMID: 38927646 PMCID: PMC11202709 DOI: 10.3390/genes15060710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/21/2024] [Accepted: 05/26/2024] [Indexed: 06/28/2024] Open
Abstract
This review article critically examines the pivotal role of chromatin organization in gene regulation, cellular differentiation, disease progression and aging. It explores the dynamic between the euchromatin and heterochromatin, coded by a complex array of histone modifications that orchestrate essential cellular processes. We discuss the pathological impacts of chromatin state misregulation, particularly in cancer and accelerated aging conditions such as progeroid syndromes, and highlight the innovative role of epigenetic therapies and artificial intelligence (AI) in comprehending and harnessing the histone code toward personalized medicine. In the context of aging, this review explores the use of AI and advanced machine learning (ML) algorithms to parse vast biological datasets, leading to the development of predictive models for epigenetic modifications and providing a framework for understanding complex regulatory mechanisms, such as those governing cell identity genes. It supports innovative platforms like CEFCIG for high-accuracy predictions and tools like GridGO for tailored ChIP-Seq analysis, which are vital for deciphering the epigenetic landscape. The review also casts a vision on the prospects of AI and ML in oncology, particularly in the personalization of cancer therapy, including early diagnostics and treatment optimization for diseases like head and neck and colorectal cancers by harnessing computational methods, AI advancements and integrated clinical data for a transformative impact on healthcare outcomes.
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Affiliation(s)
- Rogerio M. Castilho
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109-1078, USA; (L.S.C.); (C.H.S.)
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109-1078, USA
| | - Leonard S. Castilho
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109-1078, USA; (L.S.C.); (C.H.S.)
| | - Bruna H. Palomares
- Oral Diagnosis Department, Piracicaba School of Dentistry, State University of Campinas, Piracicaba 13414-903, Sao Paulo, Brazil;
| | - Cristiane H. Squarize
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109-1078, USA; (L.S.C.); (C.H.S.)
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109-1078, USA
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Smadja DM. Bone Marrow Very Small Embryonic-Like Stem Cells: New Generation of Autologous Cell Therapy Soon Ready for Prime Time? Stem Cell Rev Rep 2019; 13:198-201. [PMID: 28101702 DOI: 10.1007/s12015-017-9718-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Very small embryonic-like stem cells (VSELs) are major pluripotent stem cells described in human and mouse. In this issue of Stem Cell Reviews and Reports, Shaikh and colleagues show in a valuable work that mouse bone marrow collected after 5FU treatment contains VSELs able to undergo in vitro multi-lineage differentiation into cells from all three germ layers and also in germ and hematopoietic cells. These findings are robust since no confounding factor such as feeder cell fusion with VSELs can occur here. This paper allows one to better appreciate bone marrow-VSELs differentiation potential and opens new perspectives for autologous cell therapy. Furthermore, it might help explaining lots of contradictive data from the past 20 years, in particular related to ability of bone marrow cells to differentiate into cardiomyocytes.
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Affiliation(s)
- David M Smadja
- Hematology Department, AP-HP, European Georges Pompidou Hospital, 20 rue Leblanc, 75015, Paris, France. .,Université Paris Descartes, Sorbonne Paris Cité, Paris, France. .,Inserm UMR-S1140, Paris, France.
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Labusca L, Mashayekhi K. Human adult pluripotency: Facts and questions. World J Stem Cells 2019; 11:1-12. [PMID: 30705711 PMCID: PMC6354101 DOI: 10.4252/wjsc.v11.i1.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 11/06/2018] [Accepted: 01/10/2019] [Indexed: 02/06/2023] Open
Abstract
Cellular reprogramming and induced pluripotent stem cell (IPSC) technology demonstrated the plasticity of adult cell fate, opening a new era of cellular modelling and introducing a versatile therapeutic tool for regenerative medicine. While IPSCs are already involved in clinical trials for various regenerative purposes, critical questions concerning their medium- and long-term genetic and epigenetic stability still need to be answered. Pluripotent stem cells have been described in the last decades in various mammalian and human tissues (such as bone marrow, blood and adipose tissue). We briefly describe the characteristics of human-derived adult stem cells displaying in vitro and/or in vivo pluripotency while highlighting that the common denominators of their isolation or occurrence within tissue are represented by extreme cellular stress. Spontaneous cellular reprogramming as a survival mechanism favoured by senescence and cellular scarcity could represent an adaptative mechanism. Reprogrammed cells could initiate tissue regeneration or tumour formation dependent on the microenvironment characteristics. Systems biology approaches and lineage tracing within living tissues can be used to clarify the origin of adult pluripotent stem cells and their significance for regeneration and disease.
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Affiliation(s)
- Luminita Labusca
- National Institute of Research and Development for Advanced Technical Physics Iasi, Iasi 700349, Romania.
| | - Kaveh Mashayekhi
- Systems Biomedical Informatics and Modeling, Frankfurt D-45367, Germany
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Vasculogenic Stem and Progenitor Cells in Human: Future Cell Therapy Product or Liquid Biopsy for Vascular Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1201:215-237. [PMID: 31898789 DOI: 10.1007/978-3-030-31206-0_11] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
New blood vessel formation in adults was considered to result exclusively from sprouting of preexisting endothelial cells, a process referred to angiogenesis. Vasculogenesis, the formation of new blood vessels from endothelial progenitor cells, was thought to occur only during embryonic life. Discovery of adult endothelial progenitor cells (EPCs) in 1997 opened the door for cell therapy in vascular disease. Endothelial progenitor cells contribute to vascular repair and are now well established as postnatal vasculogenic cells in humans. It is now admitted that endothelial colony-forming cells (ECFCs) are the vasculogenic subtype. ECFCs could be used as a cell therapy product and also as a liquid biopsy in several vascular diseases or as vector for gene therapy. However, despite a huge interest in these cells, their tissue and molecular origin is still unclear. We recently proposed that endothelial progenitor could come from very small embryonic-like stem cells (VSELs) isolated in human from CD133 positive cells. VSELs are small dormant stem cells related to migratory primordial germ cells. They have been described in bone marrow and other organs. This chapter discusses the reported findings from in vitro data and also preclinical studies that aimed to explore stem cells at the origin of vasculogenesis in human and then explore the potential use of ECFCs to promote newly formed vessels or serve as liquid biopsy to understand vascular pathophysiology and in particular pulmonary disease and haemostasis disorders.
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Teofili L, Silini AR, Bianchi M, Valentini CG, Parolini O. Incorporating placental tissue in cord blood banking for stem cell transplantation. Expert Rev Hematol 2018; 11:649-661. [PMID: 29856650 DOI: 10.1080/17474086.2018.1483717] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Human term placenta is comprised of various tissues from which different cells can be obtained, including hematopoietic stem cells and mesenchymal stem/stromal cells (MSCs). Areas covered: This review will discuss the possibility to incorporate placental tissue cells in cord blood banking. It will discuss general features of human placenta, with a brief review of the immune cells at the fetal-maternal interface and the different cell populations isolated from placenta, with a particular focus on MSCs. It will address the question as to why placenta-derived MSCs should be banked with their hematopoietic counterparts. It will discuss clinical trials which are studying safety and efficacy of placenta tissue-derived MSCs in selected diseases, and preclinical studies which have proven their therapeutic properties in other diseases. It will discuss banking of umbilical cord blood and raise several issues for improvement, and the applications of cord blood cells in non-malignant disorders. Expert commentary: Umbilical cord blood banking saves lives worldwide. The concomitant banking of non-hematopoietic cells from placenta, which could be applied therapeutically in the future, alone or in combination to their hematopoietic counterparts, could exploit current banking processes while laying the foundation for clinical trials exploring placenta-derived cell therapies in regenerative medicine.
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Affiliation(s)
- Luciana Teofili
- a Policlinico Universitario A. Gemelli IRCCS , Banca del Sangue di Cordone Ombelicale UNICATT, Università Cattolica del Sacro Cuore , Rome , Italy
| | - Antonietta R Silini
- b Centro di Ricerca "E. Menni" Fondazione Poliambulanza - Istituto Ospedaliero , Brescia , Italy
| | - Maria Bianchi
- c Policlinico Universitario A. Gemelli IRCCS, Banca del Sangue di Cordone Ombelicale UNICATT , Rome , Italy
| | | | - Ornella Parolini
- b Centro di Ricerca "E. Menni" Fondazione Poliambulanza - Istituto Ospedaliero , Brescia , Italy.,d Istituto di Anatomia Umana e Biologia Cellulare Facoltà di Medicina e chirurgia "A. Gemelli" , Università Cattolica del Sacro Cuore , Rome , Italy
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Human very Small Embryonic-like Cells Support Vascular Maturation and Therapeutic Revascularization Induced by Endothelial Progenitor Cells. Stem Cell Rev Rep 2018; 13:552-560. [PMID: 28303468 DOI: 10.1007/s12015-017-9731-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Very small embryonic-like stem cells (VSELs) are major pluripotent stem cells defined as cells of small size being Lineage- negative, CD133-positive, and CD45-negative. We previously described that human bone marrow VSELs were able to differentiate into endothelial cells and promoted post-ischemic revascularization in mice with surgically induced critical limb ischemia. In the present work, we isolated bone marrow VSELs from patients with critical limb ischemia and studied their ability to support endothelial progenitor cells therapeutic capacity and revascularization potential. Sorted bone marrow VSELs cultured in angiogenic media were co-injected with endothelial progenitor cells and have been show to trigger post-ischemic revascularization in immunodeficient mice, and support vessel formation in vivo in Matrigel implants better than human bone marrow mesenchymal stem cells. In conclusion, VSELs are a potential new source of therapeutic cells that may give rise to cells of the endothelial and perivascular lineage in humans. VSELs are the first real vasculogenic stem cells able to differentiate in endothelial and perivascular lineage in human adult described from now. Thus, because VSELs presence have been proposed in adult tissues, we think that VSELs are CD45 negative stem cells able to give rise to vascular regeneration in human tissues and vessels.
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Very Small Embryonic-like Stem Cells Are Mobilized in Human Peripheral Blood during Hypoxemic COPD Exacerbations and Pulmonary Hypertension. Stem Cell Rev Rep 2018; 13:561-566. [PMID: 28285391 DOI: 10.1007/s12015-017-9732-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Very small embryonic-like stem cells (VSELs) are major pluripotent stem cells involved in vascular and tissue regeneration and constitute a recruitable pool of stem/progenitor cells with putative instrumental role in organ repair. Here, we hypothesized that VSELs might be mobilized from the bone marrow (BM) to peripheral blood (PB) in patients with hypoxic lung disease or pulmonary hypertension (PH). The objective of the present study was then to investigate the changes in VSELs number in peripheral blood of patients with hypoxic lung disease and PH. We enrolled 26 patients with Chronic Obstructive Pulmonary Disease (COPD) with or without hypoxemia, 13 patients with PH and 20 controls without any respiratory or cardiovascular diseases. In PH patients, VSELs levels have been determined during right heart catheterization in pulmonary blood and PB. For this purpose, mononuclear cells were separated by density gradient and VSELs have been quantified by using a multiparametric flow cytometry approach. The number of PB-VSELs in hypoxic COPD patients was significantly increased compared with non-hypoxic COPD patients or controls (p = 0.0055). In patients with PH, we did not find any difference in VSELs numbers between arterial pulmonary blood and venous PB (p = 0.93). However, we found an increase in VSELs in the peripheral blood of patients with PH (p = 0.03). In conclusion, we unraveled that circulating VSELs were increased in peripheral blood of patients with hypoxic COPD or with PH. Thus, VSELs may serve as a reservoir of pluripotent stem cells that can be recruited into PB and may play an important role in promoting lung repair.
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Fisch SC, Gimeno ML, Phan JD, Simerman AA, Dumesic DA, Perone MJ, Chazenbalk GD. Pluripotent nontumorigenic multilineage differentiating stress enduring cells (Muse cells): a seven-year retrospective. Stem Cell Res Ther 2017; 8:227. [PMID: 29041955 PMCID: PMC5646122 DOI: 10.1186/s13287-017-0674-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Multilineage differentiating stress enduring (Muse) cells, discovered in the spring of 2010 at Tohoku University in Sendai, Japan, were quickly recognized by scientists as a possible source of pluripotent cells naturally present within mesenchymal tissues. Muse cells normally exist in a quiescent state, singularly activated by severe cellular stress in vitro and in vivo. Muse cells have the capacity for self-renewal while maintaining pluripotent cell characteristics indicated by the expression of pluripotent stem cell markers. Muse cells differentiate into cells representative of all three germ cell layers both spontaneously and under media-specific induction. In contrast to embryonic stem and induced pluripotent stem cells, Muse cells exhibit low telomerase activity, a normal karyotype, and do not undergo tumorigenesis once implanted in SCID mice. Muse cells efficiently home into damaged tissues and differentiate into specific cells leading to tissue regeneration and functional recovery as described in different animal disease models (i.e., fulminant hepatitis, muscle degeneration, skin ulcers, liver cirrhosis, cerebral stroke, vitiligo, and focal segmental glomerulosclerosis). Circulating Muse cells have been detected in peripheral blood, with higher levels present in stroke patients during the acute phase. Furthermore, Muse cells have inherent immunomodulatory properties, which could contribute to tissue generation and functional repair in vivo. Genetic studies in Muse cells indicate a highly conserved cellular mechanism as seen in more primitive organisms (yeast, Saccharomyces cerevisiae, Caenorhabditis elegans, chlamydomonas, Torpedo californica, drosophila, etc.) in response to cellular stress and acute injury. This review details the molecular and cellular properties of Muse cells as well as their capacity for tissue repair and functional recovery, highlighting their potential for clinical application in regenerative medicine.
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Affiliation(s)
- Samantha C. Fisch
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, The University of California, 10833 Le Conte Ave, Box 951740, Los Angeles, CA 90095-1740 USA
| | - María L. Gimeno
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)—CONICET—Partner Institute of the Max Planck Society, Polo Científico Tecnológico, Godoy Cruz 2390, C1425FQD Buenos Aires, Argentina
| | - Julia D. Phan
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, The University of California, 10833 Le Conte Ave, Box 951740, Los Angeles, CA 90095-1740 USA
| | - Ariel A. Simerman
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, The University of California, 10833 Le Conte Ave, Box 951740, Los Angeles, CA 90095-1740 USA
| | - Daniel A. Dumesic
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, The University of California, 10833 Le Conte Ave, Box 951740, Los Angeles, CA 90095-1740 USA
| | - Marcelo J. Perone
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)—CONICET—Partner Institute of the Max Planck Society, Polo Científico Tecnológico, Godoy Cruz 2390, C1425FQD Buenos Aires, Argentina
| | - Gregorio D. Chazenbalk
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, The University of California, 10833 Le Conte Ave, Box 951740, Los Angeles, CA 90095-1740 USA
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Abouzaripour M, Pasbakhsh P, Atlasi N, Shahverdi AH, Mahmoudi R, Kashani IR. In Vitro Differentiation of Insulin Secreting Cells from Mouse Bone Marrow Derived Stage-Specific Embryonic Antigen 1 Positive Stem Cells. CELL JOURNAL 2016; 17:701-10. [PMID: 26862529 PMCID: PMC4746420 DOI: 10.22074/cellj.2016.3842] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 02/02/2015] [Indexed: 01/08/2023]
Abstract
OBJECTIVE Bone marrow has recently been recognized as a novel source of stem cells for the treatment of wide range of diseases. A number of studies on murine bone mar- row have shown a homogenous population of rare stage-specific embryonic antigen 1 (SSEA-1) positive cells that express markers of pluripotent stem cells. This study focuses on SSEA-1 positive cells isolated from murine bone marrow in an attempt to differentiate them into insulin-secreting cells (ISCs) in order to investigate their differentiation potential for future use in cell therapy. MATERIALS AND METHODS This study is an experimental research. Mouse SSEA-1 positive cells were isolated by Magnetic-activated cell sorting (MACS) followed by characteriza- tion with flow cytometry. Induced SSEA-1 positive cells were differentiated into ISCs with specific differentiation media. In order to evaluate differentiation quality and analysis, dithizone (DTZ) staining was use, followed by reverse transcription polymerase chain reaction (RT-PCR), immunocytochemistry and insulin secretion assay. Statistical results were analyzed by one-way ANOVA. RESULTS The results achieved in this study reveal that mouse bone marrow contains a population of SSEA-1 positive cells that expresses pluripotent stem cells markers such as SSEA-1, octamer-binding transcription factor 4 (OCT-4) detected by immunocytochem- istry and C-X-C chemokine receptor type 4 (CXCR4) and stem cell antigen-1 (SCA-1) detected by flow cytometric analysis. SSEA-1 positive cells can differentiate into ISCs cell clusters as evidenced by their DTZ positive staining and expression of genes such as Pdx1 (pancreatic transcription factors), Ngn3 (endocrine progenitor marker), Insulin1 and Insulin2 (pancreaticβ-cell markers). Additionally, our results demonstrate expression of Pdx1 and Glut2 protein and insulin secretion in response to a glucose challenge in the differentiated cells. CONCLUSION Our study clearly demonstrates the potential of SSEA-1 positive cells to differentiate into insulin secreting cells in defined culture conditions for clinical ap- plications.
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Affiliation(s)
- Morteza Abouzaripour
- Department of Anatomical Sciences, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Parichehr Pasbakhsh
- Department of Anatomical Sciences, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nader Atlasi
- Department of Anatomical Sciences, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdol Hossein Shahverdi
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Medicine, ACECR, Tehran, Iran
| | - Reza Mahmoudi
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Iraj Ragerdi Kashani
- Department of Anatomical Sciences, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Identification of New Rat Bone Marrow-Derived Population of Very Small Stem Cell with Oct-4A and Nanog Expression by Flow Cytometric Platforms. Stem Cells Int 2015; 2016:5069857. [PMID: 26633976 PMCID: PMC4655074 DOI: 10.1155/2016/5069857] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 07/05/2015] [Accepted: 07/08/2015] [Indexed: 01/17/2023] Open
Abstract
Very small embryonic-like stem cells (VSELs) represent a unique rare population of adult stem cells (SCs) sharing several structural, genetic, biochemical, and functional properties with embryonic SCs and have been identified in several adult murine and human tissues. However, rat bone marrow- (BM-) derived SCs closely resembling murine or human VSELs have not been described. Thus, we employed multi-instrumental flow cytometric approach including classical and imaging cytometry and we established that newly identified population of nonhematopoietic cells expressing CD106 (VCAM-I) antigen contains SCs with very small size, expressing markers of pluripotency (Oct-4A and Nanog) on both mRNA and protein levels that indicate VSEL population. Based on our experience in both murine and human VSEL isolation procedures by fluorescence-activated cell sorting (FACS), we also optimized sorting protocol for separation of CD45−/Lin−/CD106+ rat BM-derived VSELs from wild type and eGFP-expressing rats, which are often used as donor animals for cell transplantations in regenerative studies in vivo. Thus, this is a first study identifying multiantigenic phenotype and providing sorting protocols for isolation VSELs from rat BM tissue for further examining of their functional properties in vitro as well as regenerative capacity in distinct in vivo rat models of tissue injury.
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Maj M, Schneider G, Ratajczak J, Suszynska M, Kucia M, Ratajczak MZ. The cell cycle- and insulin-signaling-inhibiting miRNA expression pattern of very small embryonic-like stem cells contributes to their quiescent state. Exp Biol Med (Maywood) 2015; 240:1107-1111. [PMID: 25966979 PMCID: PMC4935278 DOI: 10.1177/1535370215584940] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 03/23/2015] [Indexed: 11/15/2022] Open
Abstract
Murine Oct4(+), very small embryonic-like stem cells (VSELs), are a quiescent stem cell population that requires a supportive co-culture layer to proliferate and/or to differentiate in vitro. Gene expression studies have revealed that the quiescence of these cells is due to changes in expression of parentally imprinted genes, including genes involved in cell cycle regulation and insulin and insulin-like growth factor signaling (IIS). To investigate the role of microRNAs (miRNAs) in VSEL quiescence, we performed miRNA studies in highly purified VSELs and observed a unique miRNA expression pattern in these cells. Specifically, we observed significant differences in the expression of certain miRNA species (relative to a reference cell population), including (i) miRNA-25_1 and miRNA-19 b, whose downregulation has the effect of upregulating cell cycle checkpoint genes and (ii) miRNA-675-3 p and miRNA-675-5 p, miRNA-292-5 p, miRNA-184, and miRNA-125 b, whose upregulation attenuates IIS. These observations are important for understanding the biology of these cells and for developing efficient ex vivo expansion strategies for VSELs isolated from adult tissues.
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Affiliation(s)
- Magdalena Maj
- Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Gabriela Schneider
- Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Janina Ratajczak
- Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Malwina Suszynska
- Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Magda Kucia
- Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA Department of Regenerative Medicine, Warsaw Medical University, Warsaw 02-091, Poland
| | - Mariusz Z Ratajczak
- Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA Department of Regenerative Medicine, Warsaw Medical University, Warsaw 02-091, Poland
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Wang J, Liu X, Lu H, Jiang C, Cui X, Yu L, Fu X, Li Q, Wang J. CXCR4(+)CD45(-) BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice. Brain Behav Immun 2015; 45:98-108. [PMID: 25526817 PMCID: PMC4342301 DOI: 10.1016/j.bbi.2014.12.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 12/05/2014] [Accepted: 12/10/2014] [Indexed: 02/07/2023] Open
Abstract
Cell-based therapy is considered to be a promising therapeutic strategy for stroke treatment. Although unfractionated bone marrow mononuclear cells (BMMNCs) have been tried in both preclinical and clinical trials, the effective subpopulations need to be identified. In this study, we used fluorescence-activated cell sorting to harvest the CXCR4(+)CD45(+) and CXCR4(+)CD45(-) BMMNC subpopulations from transgenic mice that express enhanced green fluorescent protein. We then allogeneically grafted unfractionated BMMNCs or a subpopulation into mice subjected to transient middle cerebral artery occlusion (tMCAO) and compared the effects on stroke outcomes. We found that CXCR4(+)CD45(-) BMMNCs, but not CXCR4(+)CD45(+) BMMNCs, more effectively reduced infarction volume and neurologic deficits than did unfractionated BMMNCs. Brain tissue from the ischemic hemisphere of mice treated with CXCR4(+)CD45(-) BMMNCs had higher levels of vascular endothelial growth factor and lower levels of TNF-α than did tissue from mice treated with unfractionated BMMNCs. In contrast, CXCR4(+)CD45(+) BMMNCs showed an increase in TNF-α. Additionally, CXCR4(+)CD45(+) and CXCR4(+)CD45(-) populations exhibited more robust migration into the lesion areas and were better able to express cell-specific markers of different linages than were the unfractionated BMMNCs. Endothelial and astrocyte cell markers did not colocalize with eGFP(+) cells in the brains of tMCAO mice that received CXCR4(+)CD45(+) BMMNCs. In vitro, the CXCR4(+)CD45(-) BMMNCs expressed significantly more Oct-4 and Nanog mRNA than did the unfractionated BMMNCs. However, we did not detect gene expression of these two pluripotent markers in CXCR4(+)CD45(+) BMMNCs. Taken together, our study shows for the first time that the CXCR4(+)CD45(-) BMMNC subpopulation is superior to unfractionated BMMNCs in ameliorating cerebral damage in a mouse model of tMCAO and could represent a new therapeutic approach for stroke treatment.
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Affiliation(s)
- Jianping Wang
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
| | - Xi Liu
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Hong Lu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Chao Jiang
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China,Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Xiaobing Cui
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Lie Yu
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xiaojie Fu
- Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Qian Li
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jian Wang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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Simerman AA, Dumesic DA, Chazenbalk GD. Pluripotent muse cells derived from human adipose tissue: a new perspective on regenerative medicine and cell therapy. Clin Transl Med 2014; 3:12. [PMID: 24940477 PMCID: PMC4041046 DOI: 10.1186/2001-1326-3-12] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 05/14/2014] [Indexed: 12/18/2022] Open
Abstract
In 2010, Multilineage Differentiating Stress Enduring (Muse) cells were introduced to the scientific community, offering potential resolution to the issue of teratoma formation that plagues both embryonic stem (ES) and induced pluripotent (iPS) stem cells. Isolated from human bone marrow, dermal fibroblasts, adipose tissue and commercially available adipose stem cells (ASCs) under severe cellular stress conditions, Muse cells self-renew in a controlled manner and do not form teratomas when injected into immune-deficient mice. Furthermore, Muse cells express classic pluripotency markers and differentiate into cells from the three embryonic germ layers both spontaneously and under media-specific induction. When transplanted in vivo, Muse cells contribute to tissue generation and repair. This review delves into the aspects of Muse cells that set them apart from ES, iPS, and various reported adult pluripotent stem cell lines, with specific emphasis on Muse cells derived from adipose tissue (Muse-AT), and their potential to revolutionize the field of regenerative medicine and stem cell therapy.
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Affiliation(s)
- Ariel A Simerman
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California, 10833 Le Conte Ave, Box 951740, Los Angeles, CA 90095-1740, USA
| | - Daniel A Dumesic
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California, 10833 Le Conte Ave, Box 951740, Los Angeles, CA 90095-1740, USA
| | - Gregorio D Chazenbalk
- Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California, 10833 Le Conte Ave, Box 951740, Los Angeles, CA 90095-1740, USA
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Simerman AA, Perone MJ, Gimeno ML, Dumesic DA, Chazenbalk GD. A mystery unraveled: nontumorigenic pluripotent stem cells in human adult tissues. Expert Opin Biol Ther 2014; 14:917-29. [PMID: 24745973 DOI: 10.1517/14712598.2014.900538] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Embryonic stem cells and induced pluripotent stem cells have emerged as the gold standard of pluripotent stem cells and the class of stem cell with the highest potential for contribution to regenerative and therapeutic application; however, their translational use is often impeded by teratoma formation, commonly associated with pluripotency. We discuss a population of nontumorigenic pluripotent stem cells, termed Multilineage Differentiating Stress Enduring (Muse) cells, which offer an innovative and exciting avenue of exploration for the potential treatment of various human diseases. AREAS COVERED This review discusses the origin of Muse cells, describes in detail their various unique characteristics, and considers future avenues of their application and investigation with respect to what is currently known of adult pluripotent stem cells in scientific literature. We begin by defining cell potency, then discuss both mesenchymal and various reported populations of pluripotent stem cells, and finally delve into Muse cells and the characteristics that set them apart from their contemporaries. EXPERT OPINION Muse cells derived from adipose tissue (Muse-AT) are efficiently, routinely and painlessly isolated from human lipoaspirate material, exhibit tripoblastic differentiation both spontaneously and under media-specific induction, and do not form teratomas. We describe qualities specific to Muse-AT cells and their potential impact on the field of regenerative medicine and cell therapy.
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Affiliation(s)
- Ariel A Simerman
- The University of California, David Geffen School of Medicine, Department of Obstetrics and Gynecology , 10833 Le Conte Ave, Box 951740, Los Angeles, CA 90095-1740 , USA +1 310 206 3670 ;
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Havens AM, Sun H, Shiozawa Y, Jung Y, Wang J, Mishra A, Jiang Y, O'Neill DW, Krebsbach PH, Rodgerson DO, Taichman RS. Human and murine very small embryonic-like cells represent multipotent tissue progenitors, in vitro and in vivo. Stem Cells Dev 2014; 23:689-701. [PMID: 24372153 DOI: 10.1089/scd.2013.0362] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
The purpose of this study was to determine the lineage progression of human and murine very small embryonic-like (HuVSEL or MuVSEL) cells in vitro and in vivo. In vitro, HuVSEL and MuVSEL cells differentiated into cells of all three embryonic germ layers. HuVSEL cells produced robust mineralized tissue of human origin compared with controls in calvarial defects. Immunohistochemistry demonstrated that the HuVSEL cells gave rise to neurons, adipocytes, chondrocytes, and osteoblasts within the calvarial defects. MuVSEL cells were also able to differentiate into similar lineages. First round serial transplants of MuVSEL cells into irradiated osseous sites demonstrated that ∼60% of the cells maintained their VSEL cell phenotype while other cells differentiated into multiple tissues at 3 months. Secondary transplants did not identify donor VSEL cells, suggesting limited self renewal but did demonstrate VSEL cell derivatives in situ for up to 1 year. At no point were teratomas identified. These studies show that VSEL cells produce multiple cellular structures in vivo and in vitro and lay the foundation for future cell-based regenerative therapies for osseous, neural, and connective tissue disorders.
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Affiliation(s)
- Aaron M Havens
- 1 Department of Periodontics and Oral Medicine, University of Michigan , School of Dentistry, Ann Arbor, Michigan
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Mesenchymal stromal/stem cells markers in the human bone marrow. Cytotherapy 2013; 15:292-306. [PMID: 23312449 DOI: 10.1016/j.jcyt.2012.11.009] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Revised: 10/17/2012] [Accepted: 11/19/2012] [Indexed: 12/16/2022]
Abstract
BACKGROUND AIMS Mesenchymal stromal/stem cells (MSCs) can be isolated from human bone marrow (BM), expanded ex vivo and identified via numerous surface antigens. Despite the importance of these cells in regenerative therapy programs, it is unclear whether the cell membrane signature defining MSC preparations ex vivo is determined during culture or may reflect an in vivo counterpart. BM-MSC phenotype in vivo requires further investigation. METHODS To characterize cells in their natural BM environment, we performed multi-parametric immunohistochemistry on trabecular bone biopsy specimens from multiple donors and described cells by different morphology and micro-anatomic localization in relationship to a precise pattern of MSC antigen expression. RESULTS Microscopically examined high-power field marrow sections revealed an overlapping in vivo expression of antigens characterizing ex vivo expanded BM-MSCs, including CD10, CD73, CD140b, CD146, GD2 and CD271. Expanding this panel to proteins associated with pluripotency, such as Oct4, Nanog and SSEA-4, we were able to identify different cellular populations in the human trabecular bone and BM expressing different progenitor cell markers. CONCLUSIONS Targeting several multipotency and pluripotency markers, we found that the BM contains identifiable and distinct progenitor cells further justifying their introduction for a wide range of applications in regenerative medicine.
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Sarnowska A, Jablonska A, Jurga M, Dainiak M, Strojek L, Drela K, Wright K, Tripathi A, Kumar A, Jungvid H, Lukomska B, Forraz N, McGuckin C, Domanska-Janik K. Encapsulation of Mesenchymal Stem Cells by Bioscaffolds Protects Cell Survival and Attenuates Neuroinflammatory Reaction in Injured Brain Tissue after Transplantation. Cell Transplant 2013; 22 Suppl 1:S67-82. [DOI: 10.3727/096368913x672172] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Since the brain is naturally inefficient in regenerating functional tissue after injury or disease, novel restorative strategies including stem cell transplantation and tissue engineering have to be considered. We have investigated the use of such strategies in order to achieve better functional repair outcomes. One of the fundamental challenges of successful transplantation is the delivery of cells to the injured site while maintaining cell viability. Classical cell delivery methods of intravenous or intraparenchymal injections are plagued by low engraftment and poor survival of transplanted stem cells. Novel implantable devices such as 3D bioactive scaffolds can provide the physical and metabolic support required for successful progenitor cell engraftment, proliferation, and maturation. In this study, we performed in situ analysis of laminin-linked dextran and gelatin macroporous scaffolds. We revealed the protective action of gelatin–laminin (GL) scaffolds seeded with mesenchymal stem cells derived from donated human Wharton's jelly (hUCMSCs) against neuroinflammatory reactions of injured mammalian brain tissue. These bioscaffolds have been implanted into (i) intact and (ii) ischemic rat hippocampal organotypic slices and into the striatum of (iii) normal and (iv) focally injured brains of adult Wistar rats. We found that transplantation of hUCMSCs encapsulated in GL scaffolds had a significant impact on the prevention of glial scar formation (low glial acidic fibrillary protein) and in the reduction of neuroinflammation (low interleukin-6 and the microglial markers ED1 and Iba1) in the recipient tissue. Moreover, implantation of hUCMSCs encapsulated within GL scaffolds induced matrix metalloproteinase-2 and -9 proteolytic activities in the surrounding brain tissue. This facilitated scaffold biodegradation while leaving the remaining grafted hUCMSCs untouched. In conclusion, transplanting GL scaffolds preseeded with hUCMSCs into mammalian brain tissue escaped the host's immune system and protected neural tissue from neuroinflammatory injury. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation.
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Affiliation(s)
- Anna Sarnowska
- NeuroRepair Department, Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Anna Jablonska
- NeuroRepair Department, Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Marcin Jurga
- Cell Therapy Research Institute, Meyzieu-Lyon, France
| | | | - Lukasz Strojek
- NeuroRepair Department, Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Katarzyna Drela
- NeuroRepair Department, Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | | | - Anuj Tripathi
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, India
| | - Ashok Kumar
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, India
| | | | - Barbara Lukomska
- NeuroRepair Department, Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Nico Forraz
- Cell Therapy Research Institute, Meyzieu-Lyon, France
| | | | - Krystyna Domanska-Janik
- NeuroRepair Department, Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
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Havens AM, Shiozawa Y, Jung Y, Sun H, Wang J, McGee S, Mishra A, Taichman LS, Danciu T, Jiang Y, Yavanian G, Leary E, Krebsbach PH, Rodgerson D, Taichman RS. Human very small embryonic-like cells generate skeletal structures, in vivo. Stem Cells Dev 2012; 22:622-30. [PMID: 23020187 DOI: 10.1089/scd.2012.0327] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Human very small embryonic-like (hVSEL) cells are a resident population of multipotent stem cells in the bone marrow involved in the turnover and regeneration of tissues. The levels of VSEL cells in blood are greatly increased in response to injury, and they have been shown to repair injured tissues. Adult hVSEL cells, SSEA-4(+)/CD133(+)/CXCR4(+)/Lin(-)/CD45(-), express the pluripotency markers (Oct-4 and Nanog) and may be able to differentiate into cells from all 3 germ lineages. hVSEL cells isolated from blood by apheresis following granulocyte-colony-stimulating factor mobilization were fractionated and enriched by elutriation and fluorescence activated cell sorting. Collagen sponge scaffolds containing 2,000-30,000 hVSEL cells were implanted into cranial defects generated in SCID mice. Analysis by microcomputed tomography showed that a cell population containing VSEL cells produced mineralized tissue within the cranial defects compared with controls at 3 months. Histologic studies showed significant bone formation and cellular organization within the defects compared with cellular or scaffold controls alone. Antibodies to human leukocyte antigens demonstrated that the newly generated tissues were of human origin. Moreover, human osteocalcin was identified circulating in the peripheral blood. There was evidence that some level of hVSEL cells migrated away from the defect site, using quantitative real-time polymerase chain reaction to detect for human-specific Alu sequences. This study demonstrates that hVSEL cells are able to generate human bone tissue in a mouse model of skeletal repair. These studies lay the foundation for future cell-based regenerative therapies for osseous and connective tissue disorders, including trauma and degenerative conditions, such as osteoporosis, fracture repair, and neoplastic repair.
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Affiliation(s)
- Aaron M Havens
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109-1078, USA
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Taichman RS, Wang Z, Shiozawa Y, Jung Y, Song J, Balduino A, Wang J, Patel LR, Havens AM, Kucia M, Ratajczak MZ, Krebsbach PH. Prospective identification and skeletal localization of cells capable of multilineage differentiation in vivo. Stem Cells Dev 2011; 19:1557-70. [PMID: 20446812 DOI: 10.1089/scd.2009.0445] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
A prospective in vivo assay was used to identify cells with potential for multiple lineage differentiation. With this assay, it was first determined that the 5-fluorouracil resistant cells capable of osseous tissue formation in vivo also migrated toward stromal derived factor-1 (SDF-1) in vitro. In parallel, an isolation method based on fluorescence-activated cell sorting was employed to identify a very small cell embryonic-like Lin-/Sca-1+CD45- cell that with as few as 500 cells was capable of forming bone-like structures in vivo. Differential marrow fractionation studies determined that the majority of the Lin-Sca-1+CD45- cells reside in the subendosteal regions of marrow. To determine whether these cells were capable of differentiating into multiple lineages, stromal cells harvested from Col2.3 Delta TK mice were implanted with a gelatin sponge into SCID mice to generate thymidine kinase sensitive ossicles. At 1.5 months, 2,000 green fluorescent protein (GFP)+ Lin-Sca-1+CD45- cells were injected into the ossicles. At harvest, colocalization of GFP-expressing cells with antibodies to the osteoblast-specific marker Runx-2 and the adipocyte marker PPAP gamma were observed. Based on the ability of the noncultured cells to differentiate into multiple mesenchymal lineages in vivo and the ability to generate osseous tissues at low density, we propose that this population fulfills many of the characteristics of mesenchymal stem cells.
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Affiliation(s)
- Russell S Taichman
- Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, Michigan 48109-1078, USA.
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Sueblinvong V, Weiss DJ. Stem cells and cell therapy approaches in lung biology and diseases. Transl Res 2010; 156:188-205. [PMID: 20801416 PMCID: PMC4201367 DOI: 10.1016/j.trsl.2010.06.007] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2010] [Revised: 06/14/2010] [Accepted: 06/16/2010] [Indexed: 12/19/2022]
Abstract
Cell-based therapies with embryonic or adult stem cells, including induced pluripotent stem cells, have emerged as potential novel approaches for several devastating and otherwise incurable lung diseases, including emphysema, pulmonary fibrosis, pulmonary hypertension, and the acute respiratory distress syndrome. Although initial studies suggested engraftment of exogenously administered stem cells in lung, this is now generally felt to be a rare occurrence of uncertain physiologic significance. However, more recent studies have demonstrated paracrine effects of administered cells, including stimulation of angiogenesis and modulation of local inflammatory and immune responses in mouse lung disease models. Based on these studies and on safety and initial efficacy data from trials of adult stem cells in other diseases, groundbreaking clinical trials of cell-based therapy have been initiated for pulmonary hypertension and for chronic obstructive pulmonary disease. In parallel, the identity and role of endogenous lung progenitor cells in development and in repair from injury and potential contribution as lung cancer stem cells continue to be elucidated. Most recently, novel bioengineering approaches have been applied to develop functional lung tissue ex vivo. Advances in each of these areas will be described in this review with particular reference to animal models.
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Key Words
- aec, alveolar epithelial cell
- ali, acute lung injury
- ards, acute respiratory distress syndrome
- basc, bronchioalveolar stem cell
- ccsp, clara cell secretory protein
- cf, cystic fibrosis
- cftr, cystic fibrosis transmembrane conductance regulator
- clp, cecal ligation and puncture
- copd, chronic obstructive pulmonary disease
- enos, endothelial nitric oxide synthetase
- epc, endothelial progenitor cell
- esc, embryonic stem cell
- fev1, forced expiratory volume in 1 second
- fvc, forced vital capacity
- gfp, green fluorescent protein
- hsc, hematopoietic stem cell
- ipf, idiopathic pulmonary fibrosis
- kgf, keratinocyte growth factor
- lps, lipopolysaccharide
- mct, monocrotaline
- mhc, major histocompatibility complex
- msc, mesenchymal stromal (stem) cell
- ph, pulmonary hypertension
- pro-spc, pro-surfactant protein c
- sca-1, stem cell antigen-1
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Affiliation(s)
- Viranuj Sueblinvong
- Division of Pulmonary, Critical Care and Allergy, Department of Medicine, Emory University, Atlanta, GA, USA
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Machalińska A, Baumert B, Kuprjanowicz L, Wiszniewska B, Karczewicz D, Machaliński B. Potential application of adult stem cells in retinal repair--challenge for regenerative medicine. Curr Eye Res 2009; 34:748-60. [PMID: 19839868 DOI: 10.1080/02713680903050592] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Stem cells (SCs) maintain the balance among somatic cell populations in various tissues and are responsible for organ regeneration. The remarkable progress of regenerative medicine in the last few years indicates promise for the use of SCs in ophthalmic disorder treatment. This review describes the current view on hierarchy in the SC compartment and presents the latest attempts to use adult SCs in the regeneration of the retina. Research performed primarily in animal models gives hope for using similar strategies in humans. However, the search for the optimal source of SCs for cell therapy continues. We briefly discuss various potential sources of adult SCs that could be employed in regenerative medicine, particularly focusing on recently identified, very small embryonic-like SCs (VSEL-SCs). These cells are even present in the bone marrow and adult tissues of older patients and could be harvested from cord blood. We believe that VSEL-SCs, after the establishment of ex vivo expansion and differentiation protocols, could be harnessed for retina regeneration.
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Affiliation(s)
- Anna Machalińska
- Department of Histology and Embryology, Pomeranian Medical University, Szczecin, Poland
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Enzmann V, Yolcu E, Kaplan HJ, Ildstad ST. Stem cells as tools in regenerative therapy for retinal degeneration. ARCHIVES OF OPHTHALMOLOGY (CHICAGO, ILL. : 1960) 2009; 127:563-71. [PMID: 19365041 PMCID: PMC3192438 DOI: 10.1001/archophthalmol.2009.65] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To describe the use of stem cells (SCs) for regeneration of retinal degenerations. Regenerative medicine intends to provide therapies for severe injuries or chronic diseases where endogenous repair does not sufficiently restore the tissue. Pluripotent SCs, with their capacity to give rise to specialized cells, are the most promising candidates for clinical application. Despite encouraging results, a combination with up-to-date tissue engineering might be critical for ultimate success. DESIGN The focus is on the use of SCs for regeneration of retinal degenerations. Cell populations include embryonic, neural, and bone marrow-derived SCs, and engineered grafts will also be described. RESULTS Experimental approaches have successfully replaced damaged photoreceptors and retinal pigment epithelium using endogenous and exogenous SCs. CONCLUSIONS Stem cells have the potential to significantly impact retinal regeneration. A combination with bioengineering may bear even greater promise. However, ethical and scientific issues have yet to be solved.
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Affiliation(s)
- Volker Enzmann
- Department of Ophthalmology, Inselspital, University of Bern, Switzerland
| | - Esma Yolcu
- Institute for Cellular Therapeutics, University of Louisville, Louisville, KY USA
| | - Henry J. Kaplan
- Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY USA
| | - Suzanne T. Ildstad
- Institute for Cellular Therapeutics, University of Louisville, Louisville, KY USA
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Ratajczak MZ, Kucia M, Ratajczak J, Zuba-Surma EK. A multi-instrumental approach to identify and purify very small embryonic like stem cells (VSELs) from adult tissues. Micron 2009; 40:386-93. [DOI: 10.1016/j.micron.2008.09.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2008] [Accepted: 09/27/2008] [Indexed: 11/17/2022]
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Zuba-Surma EK, Kucia M, Ratajczak J, Ratajczak MZ. "Small stem cells" in adult tissues: very small embryonic-like stem cells stand up! Cytometry A 2009; 75:4-13. [PMID: 18988270 DOI: 10.1002/cyto.a.20665] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This review summarizes information regarding the rare population of very small embryonic-like stem cells (VSELs) that has been identified in adult tissues, emphasizing both their unique morphological features and potential biological significance. We focus on their pluripotent nature and expression of markers characteristic for embryonic stem cells (ESCs), epiblast (EP)SCs, and primordial germ cells (PGCs). Furthermore, we will discuss their rank in the developmental hierarchy of the SC compartment as well as their relationship to other bone marrow-derived, primitive, nonhematopoietic SCs including: (i) endothelial progenitor cells (EPCs); (ii) mesenchymal (M)SCs; (iii) multipotent adult progenitor cells (MAPCs); (iv) marrow-isolated adult multilineage inducible (MIAMIs) cells; (v) multipotent adult (MA)SCs; and (vi) OmniCytes. We will also present different populations of very "small SCs" that have been recently described in the literature (e.g., spore-like cells and Lin(-)/ALDH(high) long-term repopulating hematopoietic SCs).
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Affiliation(s)
- Ewa K Zuba-Surma
- Stem Cell Biology Institute, University of Louisville, Louisville, Kentucky 40202, USA
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Stem cells and cell therapies in lung biology and lung diseases. Ann Am Thorac Soc 2008; 5:637-67. [PMID: 18625757 DOI: 10.1513/pats.200804-037dw] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Shiozawa Y, Havens AM, Pienta KJ, Taichman RS. The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 2008; 22:941-50. [PMID: 18305549 DOI: 10.1038/leu.2008.48] [Citation(s) in RCA: 148] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In post-fetal life, hematopoiesis occurs in unique microenvironments or 'niches' in the marrow. Niches facilitate the maintenance of hematopoietic stem cells (HSCs) as unipotent, while supporting lineage commitment of the expanding blood populations. As the physical locale that regulates HSC function, the niche function is vitally important to the survival of the organism. This places considerable selective pressure on HSCs, as only those that are able to engage the niche in the appropriate context are likely to be maintained as stem cells. Since niches are central regulators of stem cell function, it is not surprising that molecular parasites like neoplasms are likely to seek out opportunities to harvest resources from the niche environment. As such, the niche may unwittingly participate in tumorigenesis as a leukemic or neoplastic niche. The niche may also promote metastasis or chemo-resistance of hematogenous neoplasms or solid tumors. This review focuses on what is known about the physical structures of the niche, how the niche participates in hematopoiesis and neoplastic growth and what molecules are involved. Further understanding of the interactions between stem cells and the niche may be useful for developing therapeutic strategies.
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Affiliation(s)
- Y Shiozawa
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, USA
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Zuba-Surma EK, Wu W, Ratajczak J, Kucia M, Ratajczak MZ. Very small embryonic-like stem cells in adult tissues-potential implications for aging. Mech Ageing Dev 2008; 130:58-66. [PMID: 18377952 DOI: 10.1016/j.mad.2008.02.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2008] [Revised: 01/24/2008] [Accepted: 02/07/2008] [Indexed: 10/22/2022]
Abstract
Recently our group identified in murine bone marrow (BM) and human cord blood (CB), a rare population of very small embryonic-like (VSEL) stem cells. We hypothesize that these cells are deposited during embryonic development in BM as a mobile pool of circulating pluripotent stem cells (PSC) that play a pivotal role in postnatal tissue turnover both of non-hematopoietic and hematopoietic tissues. During in vitro co-cultures with murine myoblastic C2C12 cells, VSELs form spheres that contain primitive stem cells. Cells isolated from these spheres may give rise to cells from all three germ layers when plated in tissue specific media. The number of murine VSELs and their ability to form spheres decreases with the age and is reduced in short-living murine strains. Thus, developmental deposition of VSELs in adult tissues may potentially play an underappreciated role in regulating the rejuvenation of senescent organs. We envision that the regenerative potential of these cells could be harnessed to decelerate aging processes.
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Affiliation(s)
- E K Zuba-Surma
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
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