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1
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Soumya BS, Gamit N, Patil M, Shreenidhi VP, Dharmarajan A, Warrier S. Modeling amyotrophic lateral sclerosis with amniotic membrane-derived mesenchymal stem cells: A novel approach for disease modeling. Exp Cell Res 2025; 446:114449. [PMID: 39961464 DOI: 10.1016/j.yexcr.2025.114449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 01/16/2025] [Accepted: 02/14/2025] [Indexed: 02/24/2025]
Abstract
Advancement of therapeutics for neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) has been predominantly hampered by the dearth of relevant disease models. Despite numerous animal models, significant challenges remain in correlating these with human disease complexities. In this study, the ALS model was created using amniotic membrane-derived mesenchymal stem cells (AM-MSCs) which were differentiated into motor neurons (MN) with specific MN induction media and transiently transfected with mutated human SOD1 G93A plasmid to induce ALS-like condition. Characterization included gene expression analysis, immunocytochemistry, flow cytometry, and Western blot. Functional assays assessed the extent of degeneration and model efficiency. AM-MSCs demonstrated multipotency and were positive for MSC markers. Upon differentiation, the expression of MN markers like MNX1, Olig2, and ChAT were found to be elevated. SOD1 G93A overexpression, downregulated MN markers, upregulated NURR1 gene, reduced acetylcholine (ACh), reduced glutathione, and elevated oxidative stress markers. This robust in-vitro ALS model derived from AM-MSCs offers an alternative to animal models to provide an efficient and cost-effective platform to conduct rapid drug screening.
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Affiliation(s)
- B S Soumya
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, 560065, India
| | - Naisarg Gamit
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, 560065, India
| | - Manasi Patil
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, 560065, India
| | - V P Shreenidhi
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, 560065, India
| | - Arun Dharmarajan
- School of Human Sciences, Faculty of Life and Physical Sciences, The University of Western Australia, Perth, WA 6009, Australia; Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia
| | - Sudha Warrier
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, 560065, India; Division of Regenerative Medicine and Cancer Stem Cells, Department of Biotechnology, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, 600116, India.
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2
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Martin EW, Rodriguez y Baena A, Reggiardo RE, Worthington AK, Mattingly CS, Poscablo DM, Krietsch J, McManus MT, Carpenter S, Kim DH, Forsberg EC. Dynamics of Chromatin Accessibility During Hematopoietic Stem Cell Differentiation Into Progressively Lineage-Committed Progeny. Stem Cells 2023; 41:520-539. [PMID: 36945732 PMCID: PMC10183972 DOI: 10.1093/stmcls/sxad022] [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: 02/06/2022] [Accepted: 02/27/2023] [Indexed: 03/23/2023]
Abstract
Epigenetic mechanisms regulate the multilineage differentiation capacity of hematopoietic stem cells (HSCs) into a variety of blood and immune cells. Mapping the chromatin dynamics of functionally defined cell populations will shed mechanistic insight into 2 major, unanswered questions in stem cell biology: how does epigenetic identity contribute to a cell type's lineage potential, and how do cascades of chromatin remodeling dictate ensuing fate decisions? Our recent work revealed evidence of multilineage gene priming in HSCs, where open cis-regulatory elements (CREs) exclusively shared between HSCs and unipotent lineage cells were enriched for DNA binding motifs of known lineage-specific transcription factors. Oligopotent progenitor populations operating between the HSCs and unipotent cells play essential roles in effecting hematopoietic homeostasis. To test the hypothesis that selective HSC-primed lineage-specific CREs remain accessible throughout differentiation, we used ATAC-seq to map the temporal dynamics of chromatin remodeling during progenitor differentiation. We observed epigenetic-driven clustering of oligopotent and unipotent progenitors into distinct erythromyeloid and lymphoid branches, with multipotent HSCs and MPPs associating with the erythromyeloid lineage. We mapped the dynamics of lineage-primed CREs throughout hematopoiesis and identified both unique and shared CREs as potential lineage reinforcement mechanisms at fate branch points. Additionally, quantification of genome-wide peak count and size revealed overall greater chromatin accessibility in HSCs, allowing us to identify HSC-unique peaks as putative regulators of self-renewal and multilineage potential. Finally, CRISPRi-mediated targeting of ATACseq-identified putative CREs in HSCs allowed us to demonstrate the functional role of selective CREs in lineage-specific gene expression. These findings provide insight into the regulation of stem cell multipotency and lineage commitment throughout hematopoiesis and serve as a resource to test functional drivers of hematopoietic lineage fate.
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Affiliation(s)
- Eric W Martin
- Institute for the Biology of Stem Cells, Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, USA
| | - Alessandra Rodriguez y Baena
- Institute for the Biology of Stem Cells, Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, USA
| | - Roman E Reggiardo
- Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, USA
| | - Atesh K Worthington
- Institute for the Biology of Stem Cells, Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, USA
| | - Connor S Mattingly
- Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, USA
| | - Donna M Poscablo
- Institute for the Biology of Stem Cells, Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, USA
| | - Jana Krietsch
- Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, USA
| | - Michael T McManus
- Department of Microbiology and Immunology, Diabetes Center, W.M. Keck Center for Noncoding RNAs, University of California San Francisco, San Francisco, CA, USA
| | - Susan Carpenter
- Institute for the Biology of Stem Cells, Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, USA
| | - Daniel H Kim
- Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, USA
| | - E Camilla Forsberg
- Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, USA
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3
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Zhang L, Ma XJN, Fei YY, Han HT, Xu J, Cheng L, Li X. Stem cell therapy in liver regeneration: Focus on mesenchymal stem cells and induced pluripotent stem cells. Pharmacol Ther 2022; 232:108004. [PMID: 34597754 DOI: 10.1016/j.pharmthera.2021.108004] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/11/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023]
Abstract
The liver has the ability to repair itself after injury; however, a variety of pathological changes in the liver can affect its ability to regenerate, and this could lead to liver failure. Mesenchymal stem cells (MSCs) are considered a good source of cells for regenerative medicine, as they regulate liver regeneration through different mechanisms, and their efficacy has been demonstrated by many animal experiments and clinical studies. Induced pluripotent stem cells, another good source of MSCs, have also made great progress in the establishment of organoids, such as liver disease models, and in drug screening. Owing to the recent developments in MSCs and induced pluripotent stem cells, combined with emerging technologies including graphene, nano-biomaterials, and gene editing, precision medicine and individualized clinical treatment may be realized in the near future.
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Affiliation(s)
- Lu Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Xiao-Jing-Nan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Yuan-Yuan Fei
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Jun Xu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Lu Cheng
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Xun Li
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China.
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4
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Chiabotto G, Ceccotti E, Tapparo M, Camussi G, Bruno S. Human Liver Stem Cell-Derived Extracellular Vesicles Target Hepatic Stellate Cells and Attenuate Their Pro-fibrotic Phenotype. Front Cell Dev Biol 2021; 9:777462. [PMID: 34796180 PMCID: PMC8593217 DOI: 10.3389/fcell.2021.777462] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/13/2021] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis occurs in response to chronic liver injury and is characterized by an excessive deposition of extracellular matrix. Activated hepatic stellate cells are primarily responsible for this process. A possible strategy to counteract the development of hepatic fibrosis could be the reversion of the activated phenotype of hepatic stellate cells. Extracellular vesicles (EVs) are nanosized membrane vesicles involved in intercellular communication. Our previous studies have demonstrated that EVs derived from human liver stem cells (HLSCs), a multipotent population of adult stem cells of the liver with mesenchymal-like phenotype, exert in vivo anti-fibrotic activity in the liver. However, the mechanism of action of these EVs remains to be determined. We set up an in vitro model of hepatic fibrosis using a human hepatic stellate cell line (LX-2) activated by transforming growth factor-beta 1 (TGF-β1). Then, we investigated the effect of EVs obtained from HLSCs and from human bone marrow-derived mesenchymal stromal cells (MSCs) on activated LX-2. The incubation of activated LX-2 with HLSC-EVs reduced the expression level of alpha-smooth muscle actin (α-SMA). Conversely, MSC-derived EVs induced an increase in the expression of pro-fibrotic markers in activated LX-2. The analysis of the RNA cargo of HLSC-EVs revealed the presence of several miRNAs involved in the regulation of fibrosis and inflammation. Predictive target analysis indicated that several microRNAs (miRNAs) contained into HLSC-EVs could possibly target pro-fibrotic transcripts. In particular, we demonstrated that HLSC-EVs shuttled miR-146a-5p and that treatment with HLSC-EVs increased miR-146a-5p expression in LX-2. In conclusion, this study demonstrates that HLSC-EVs can attenuate the activated phenotype of hepatic stellate cells and that their biological effect may be mediated by the delivery of anti-fibrotic miRNAs, such as miR-146a-5p.
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Affiliation(s)
- Giulia Chiabotto
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| | - Elena Ceccotti
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| | - Marta Tapparo
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Torino, Turin, Italy.,Molecular Biotechnology Center, University of Torino, Turin, Italy
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5
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Stevanovic M, Kovacevic-Grujicic N, Mojsin M, Milivojevic M, Drakulic D. SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation. World J Stem Cells 2021; 13:1417-1445. [PMID: 34786152 PMCID: PMC8567447 DOI: 10.4252/wjsc.v13.i10.1417] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/15/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.
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Affiliation(s)
- Milena Stevanovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
- Chair Biochemistry and Molecular Biology, Faculty of Biology, University of Belgrade, Belgrade 11158, Serbia
- Department of Chemical and Biological Sciences, Serbian Academy of Sciences and Arts, Belgrade 11000, Serbia.
| | - Natasa Kovacevic-Grujicic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Marija Mojsin
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Milena Milivojevic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Danijela Drakulic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
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6
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Bhartiya D, Singh P, Sharma D, Kaushik A. Very small embryonic-like stem cells (VSELs) regenerate whereas mesenchymal stromal cells (MSCs) rejuvenate diseased reproductive tissues. Stem Cell Rev Rep 2021; 18:1718-1727. [PMID: 34410593 DOI: 10.1007/s12015-021-10243-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2021] [Indexed: 12/15/2022]
Abstract
Compared to embryonic and induced pluripotent stem cells, mesenchymal stem/stromal cells (MSCs) have made their presence felt with good therapeutic promise and safety profile. Transplanting MSCs has successfully helped to reverse infertility and resulted in live births in animal models and also in humans. But the underlying mechanism for their therapeutic potential is not yet clear. MSCs are not pluripotent and hence lack plasticity to differentiate into multiple adult cell types. They rather act as 'paracrine providers' to the tissue-resident stem cells since similar beneficial effects are also observed when their secretome (microvesicles or exosomes) is transplanted. Cytokines, growth factors, signaling lipids, mRNAs, and miRNAs secreted by MSCs enables tissue-resident stem cells to undergo differentiation into specific cell types. Tissue-resident stem cells include pluripotent, very small embryonic-like stem cells (VSELs) and progenitors [spermatogonial (SSCs), ovarian (OSCs) and endometrial (EnSCs) stem cells in testes, ovary and uterus respectively] which function in a subtle manner to maintain life-long tissue homeostasis and regenerate damaged (non-functional) reproductive tissues by differentiating into sperm, oocytes and endometrial epithelial cells respectively. Similar to restoring spermatogenesis, primordial follicles numbers are increased upon transplanting MSCs. Published literature suggests that MSCs do not differentiate into epithelial cells in the endometrium. Nuclear OCT-4 positive VSELs and cytoplasmic OCT-4, AXIN2 and KERATIN-19 positive epithelial progenitors have a greater role during endometrial regeneration. We propose, transplantation of MSCs simply provides growth factors/cytokines essential for the tissue-resident stem/progenitor cells to undergo differentiation into sperm, eggs and endometrial epithelial cells in the reproductive tissues.
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Affiliation(s)
- Deepa Bhartiya
- Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400012, India.
| | - Pushpa Singh
- Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400012, India
| | - Diksha Sharma
- Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400012, India
| | - Ankita Kaushik
- Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400012, India
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7
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Oraee-Yazdani S, Akhlaghpasand M, Golmohammadi M, Hafizi M, Zomorrod MS, Kabir NM, Oraee-Yazdani M, Ashrafi F, Zali A, Soleimani M. Combining cell therapy with human autologous Schwann cell and bone marrow-derived mesenchymal stem cell in patients with subacute complete spinal cord injury: safety considerations and possible outcomes. Stem Cell Res Ther 2021; 12:445. [PMID: 34372939 PMCID: PMC8351425 DOI: 10.1186/s13287-021-02515-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 07/12/2021] [Indexed: 11/22/2022] Open
Abstract
Background Cellular transplantations have promising effects on treating spinal cord injury (SCI) patients. Mesenchymal stem cells (MSCs) and Schwann cells (SCs), which have safety alongside their complementary characteristics, are suggested to be the two of the best candidates in SCI treatment. In this study, we assessed the safety and possible outcomes of intrathecal co-transplantation of autologous bone marrow MSC and SC in patients with subacute traumatic complete SCI. Methods Eleven patients with complete SCI (American Spinal Injury Association Impairment Scale (AIS); grade A) were enrolled in this study during the subacute period of injury. The patients received an intrathecal autologous combination of MSC and SC and were followed up for 12 months. We assessed the neurological changes by the American Spinal Injury Association’s (ASIA) sensory-motor scale, functional recovery by spinal cord independence measure (SCIM-III), and subjective changes along with adverse events (AE) with our checklist. Furthermore, electromyography (EMG), nerve conduction velocity (NCV), magnetic resonance imaging (MRI), and urodynamic study (UDS) were conducted for all the patients at the baseline, 6 months, and 1 year after the intervention. Results Light touch AIS score alterations were approximately the same as the pinprick changes (11.6 ± 13.1 and 12 ± 13, respectively) in 50% of the cervical and 63% of the lumbar-thoracic patients, and both were more than the motor score alterations (9.5 ± 3.3 in 75% of the cervical and 14% of the lumbar-thoracic patients). SCIM III total scores (21.2 ± 13.3) and all its sub-scores (“respiration and sphincter management” (15 ± 9.9), “mobility” (9.5 ± 13.3), and “self-care” (6 ± 1.4)) had statistically significant changes after cell injection. Our findings support that the most remarkable positive, subjective improvements were in trunk movement, equilibrium in standing/sitting position, the sensation of the bladder and rectal filling, and the ability of voluntary voiding. Our safety evaluation revealed no systemic complications, and radiological images showed no neoplastic overgrowth, syringomyelia, or pseudo-meningocele. Conclusion The present study showed that autologous SC and bone marrow-derived MSC transplantation at the subacute stage of SCI could reveal statistically significant improvement in sensory and neurological functions among the patients. It appears that using this combination of cells is safe and effective for clinical application to spinal cord regeneration during the subacute period.
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Affiliation(s)
- Saeed Oraee-Yazdani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, 1988873554, Iran.
| | - Mohammadhosein Akhlaghpasand
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, 1988873554, Iran
| | - Maryam Golmohammadi
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, 1988873554, Iran
| | - Maryam Hafizi
- Stem Cell Technology Research Centre, Tehran, Iran.,Department of Research and Development, Sodour Ahrar Shargh Company, Tehran, Iran
| | - Mina Soufi Zomorrod
- Applied cell Sciences Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Nima Mohseni Kabir
- Department of Neurosurgery, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Oraee-Yazdani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, 1988873554, Iran
| | - Farzad Ashrafi
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, 1988873554, Iran
| | - Alireza Zali
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, 1988873554, Iran.
| | - Masoud Soleimani
- Department of Hematology, Tarbiat Modares University, Tehran, Iran.
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8
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Sykova E, Cizkova D, Kubinova S. Mesenchymal Stem Cells in Treatment of Spinal Cord Injury and Amyotrophic Lateral Sclerosis. Front Cell Dev Biol 2021; 9:695900. [PMID: 34295897 PMCID: PMC8290345 DOI: 10.3389/fcell.2021.695900] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 05/31/2021] [Indexed: 01/01/2023] Open
Abstract
Preclinical and clinical studies with various stem cells, their secretomes, and extracellular vesicles (EVs) indicate their use as a promising strategy for the treatment of various diseases and tissue defects, including neurodegenerative diseases such as spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS). Autologous and allogenic mesenchymal stem cells (MSCs) are so far the best candidates for use in regenerative medicine. Here we review the effects of the implantation of MSCs (progenitors of mesodermal origin) in animal models of SCI and ALS and in clinical studies. MSCs possess multilineage differentiation potential and are easily expandable in vitro. These cells, obtained from bone marrow (BM), adipose tissue, Wharton jelly, or even other tissues, have immunomodulatory and paracrine potential, releasing a number of cytokines and factors which inhibit the proliferation of T cells, B cells, and natural killer cells and modify dendritic cell activity. They are hypoimmunogenic, migrate toward lesion sites, induce better regeneration, preserve perineuronal nets, and stimulate neural plasticity. There is a wide use of MSC systemic application or MSCs seeded on scaffolds and tissue bridges made from various synthetic and natural biomaterials, including human decellularized extracellular matrix (ECM) or nanofibers. The positive effects of MSC implantation have been recorded in animals with SCI lesions and ALS. Moreover, promising effects of autologous as well as allogenic MSCs for the treatment of SCI and ALS were demonstrated in recent clinical studies.
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Affiliation(s)
- Eva Sykova
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Dasa Cizkova
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia.,Centre for Experimental and Clinical Regenerative Medicine, University of Veterinary Medicine and Pharmacy in Kosice, Kosice, Slovakia
| | - Sarka Kubinova
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences, Prague, Czechia
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9
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Liu F, Chen H, Chen T, Lau CS, Yu FX, Chen K, Chen HP, Pan RS, Chan GCF, Zhang XY, Nie YJ. Immunotherapeutic effects of allogeneic mesenchymal stem cells on systemic lupus erythematosus. Lupus 2021; 29:872-883. [PMID: 32580680 DOI: 10.1177/0961203320928419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Mesenchymal stem cells have been applied to treat graft versus host disease as they have immunosuppressive ability and can overcome the major histocompatibility complex-histocompatibility barrier. The potential of allogeneic mesenchymal stem cells in treating systemic lupus erythematosus (SLE) was investigated in this study. MRL/lpr mice which can develop acquired SLE-like phenotypes were selected as an animal model. Mesenchymal stem cells obtained from green fluorescent protein-transgenic ICR mice were infused into MRL/lpr mice at either the early or late stage of disease. The dosage was 1 × 106/mice per infusion. Mice were stratified into six groups including negative controls and those receiving one, two, three, four or five doses at 2-weekly intervals. The phenotypes were monitored regularly. After treatment, the spleen CD3+CD4-CD8- T and CD19+ B cells of two-dose mesenchymal stem cell-treated mice were significantly lower than those of the phosphate-buffered saline control. In terms of reducing the severity of SLE such as hair loss, skin ulcers, proteinuria and anti-dsDNA level, mesenchymal stem cells given at the early stage responded better and mice receiving two doses of mesenchymal stem cells performed better than those receiving either a lower dose (one dose) or higher doses (three, four or five doses). In conclusion, early treatment and an optimal dose of mesenchymal stem cells can effectively suppress the murine SLE model.
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Affiliation(s)
- Fang Liu
- The Medical College, Guizhou University, Guiyang, China
| | - Hui Chen
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, China
| | - Tao Chen
- Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Chak-Sing Lau
- Department of Medicine, The University of Hong Kong, Pokfulam, China
| | - Fu-Xun Yu
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, China
| | - Kun Chen
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, China
| | - Hou-Ping Chen
- Department of Orthopedics, Guiyang Children's Hospital, Guiyang, China
| | - Run-Sang Pan
- Department of Orthopedics, Guiyang Children's Hospital, Guiyang, China
| | - Godfrey Chi-Fung Chan
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Xiang-Yan Zhang
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, China
| | - Ying-Jie Nie
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, China
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10
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Chiabotto G, Pasquino C, Camussi G, Bruno S. Molecular Pathways Modulated by Mesenchymal Stromal Cells and Their Extracellular Vesicles in Experimental Models of Liver Fibrosis. Front Cell Dev Biol 2020; 8:594794. [PMID: 33425900 PMCID: PMC7794013 DOI: 10.3389/fcell.2020.594794] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/06/2020] [Indexed: 12/18/2022] Open
Abstract
End-stage liver fibrosis is common to all chronic liver diseases. Since liver transplantation has several limitations, including lack of donors, immunological rejection, and high medical costs, therapeutic alternatives are needed. The administration of mesenchymal stromal cells (MSCs) has been proven effective in tissue regeneration after damage. However, the risk of uncontrolled side effects, such as cellular rejection and tumorigenesis, should be taken into consideration. A safer alternative to MSC transplantation is represented by the MSC secretome, which retains the same beneficial effect of the cell of origin, without showing any considerable side effect. The paracrine effect of MSCs is mainly carried out by secreted particles in the nanometer range, known as extracellular vesicles (EVs) that play a fundamental role in intercellular communication. In this review, we discuss the current literature on MSCs and MSC-EVs, focusing on their potential therapeutic action in liver fibrosis and on their molecular content (proteins and RNA), which contributes in reverting fibrosis and prompting tissue regeneration.
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Affiliation(s)
- Giulia Chiabotto
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Chiara Pasquino
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
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11
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Jin L, Zhao W, Ren B, Li L, Hu X, Zhang X, Cai Q, Ao Y, Yang X. Osteochondral tissue regenerated via a strategy by stacking pre-differentiated BMSC sheet on fibrous mesh in a gradient. ACTA ACUST UNITED AC 2019; 14:065017. [PMID: 31574486 DOI: 10.1088/1748-605x/ab49e2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The reconstruction of osteochondral tissue remains a challenging task in clinical therapy because of its heterogeneous structure. The best way to face the challenge is to develop a biomimetic construct to mimic the multilayered gradient from cartilage, to calcified cartilage and subchondral bone. In this study, bone marrow mesenchymal stromal cells (BMSCs) were cultured on electrospun fibrous meshes and cell sheets were incubated. The fibrous meshes were composed of 50% poly(L-lactide) and 50% gelatin, displaying excellent biocompatibility, cell affinity and degradability. Differentiation of BMSC sheets on fibrous meshes was induced chondrogenically or osteogenically. In particular, the BMSC sheets were able to be efficiently induced differentiating towards calcified cartilage by using a 1:1 (v/v) mixed medium of chondrogenic and osteogenic inductive media. Thus, a gradient 3D construct was built by stacking the differently pre-differentiated cell/mesh complexes layer by layer from top to bottom to mimic the cartilage-to-bone transition. With this gradient construct being implanted in the rabbit knee osteochondral defect, it was confirmed that it could promote the tissue regeneration with intact cartilage layer formation in comparison with the multilayered construct without a gradient. The strategy of using properly pre-differentiated BMSC sheet on fibrous mesh to build the osteochondral interface was thus suggested as being feasible and effective in mimicking its hierarchical complexity, and favored the repairing of injured joint cartilage.
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Affiliation(s)
- Le Jin
- State Key Laboratory of Organic-Inorganic Composites; Beijing Laboratory of Biomedical Materials; Beijing University of Chemical Technology, Beijing 100029, People's Republic of China
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12
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Whiting D, Chung WO, Johnson JD, Paranjpe A. Characterization of the Cellular Responses of Dental Mesenchymal Stem Cells to the Immune System. J Endod 2018; 44:1126-1131. [PMID: 29884336 DOI: 10.1016/j.joen.2018.03.018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 03/26/2018] [Accepted: 03/31/2018] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Dental stem cells have gained importance recently and are being used for various purposes in regenerative medicine and dentistry. Although much research has been done to show the various properties of these dental stem cells, the immunomodulatory properties of some of these stem cells are still unknown. This is important considering these cells are being used routinely. Therefore, the aim of this study was to investigate the interactions between the activated immune cells and 3 types of dental-derived mesenchymal stem cells: dental pulp stem cells, stem cells from human exfoliated deciduous teeth, and stem cells of the apical papilla (SCAP). METHODS SCAP, dental pulp stem cells, stem cells from human exfoliated deciduous teeth, and periodontal ligament fibroblasts were cultured, and various assays were performed including a proliferation assay, flow cytometric analysis, lactate dehydrogenase and chromium-51 cytotoxicity assays, and an enzyme-linked immunosorbent assay to evaluate the interactions of these dental stem cells when cocultured with either peripheral blood mononuclear cells or natural killer cells. RESULTS SCAP were less resistant to immune cell-mediated cytotoxicity as seen from the results obtained from the LDH and chromium-51 cytotoxicity assays. The flow cytometric analysis showed a lower resilience of SCAP to cytotoxic compounds. The enzyme-linked immunosorbent assay results demonstrated that the SCAP induced high levels of proinflammatory cytokine secretion compared with the other dental stem cells. CONCLUSIONS SCAP did not perform as well as the other dental stem cells. This could in turn affect their survival and differentiation abilities as well as their functionality. This may be an important aspect to consider when selecting dental stem cells for various regenerative procedures.
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Affiliation(s)
- Dean Whiting
- Department of Endodontics, University of Washington, Seattle, Washington
| | - Whasun Oh Chung
- Department of Oral Health Sciences, University of Washington, Seattle, Washington
| | - James D Johnson
- Department of Endodontics, University of Washington, Seattle, Washington
| | - Avina Paranjpe
- Department of Endodontics, University of Washington, Seattle, Washington.
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13
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Zhang H, Zhu T, Zhang L, Wu Q. Stromal cell‑derived factor‑1 induces matrix metalloproteinase expression in human endplate chondrocytes, cartilage endplate degradation in explant culture, and the amelioration of nucleus pulposus degeneration in vivo. Int J Mol Med 2017; 41:969-976. [PMID: 29207021 DOI: 10.3892/ijmm.2017.3278] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 11/13/2017] [Indexed: 11/05/2022] Open
Abstract
Intervertebral disc (IVD) degeneration is a strong etiological factor in chronic lower back pain. Stem cell migration toward the site of IVD degeneration for regeneration is restricted by avascularity and distance. Our previous study indicated that the expression of stromal cell‑derived factor‑1 (SDF‑1) and its receptor, C-X-C chemokine receptor type 4 (CXCR4) was upregulated in degenerated cartilage endplate (CEP) and nucleus pulposus (NP). In the present study, SDF‑1 increased CXCR4 mRNA and protein expression in human endplate chondrocytes in a dose‑dependent manner. The results of reverse transcription-quantitative polymerase chain reaction, western blotting and zymography indicated that SDF‑1 increased matrix metalloproteinase (MMP)‑1, ‑3 and ‑13 mRNA and protein expression in human endplate chondrocytes in a dose‑dependent manner. The results of zymography suggested that SDF‑1 also increased MMP‑2 and ‑9 protein expression in a dose‑dependent manner. The CXCR4‑specific chemical inhibitor AMD3100 significantly decreased the levels of MMP‑1, ‑2, ‑3, ‑9 and ‑13 expression. In a human cartilage explant culture model, SDF‑1 accelerated the degradation of extracellular matrix (ECM), and AMD3100 decreased cartilage cleavage. However, in a rat tail disc degeneration model, the injection of SDF‑1 into the NP resulted in the retention of dense areas of proteoglycan matrix and enhanced NP regeneration. These results suggest that SDF‑1, as an inflammatory cytokine, induces MMP expression in human endplate chondrocytes and that ECM remodeling in the CEP may be a favorable factor of endogenous stem cell homing into the NP for regeneration in vivo.
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Affiliation(s)
- Hua Zhang
- Department of Orthopaedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Ting Zhu
- Department of Orthopaedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Li Zhang
- Department of Clinical Laboratory, Hangzhou Red Cross Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, P.R. China
| | - Qionghua Wu
- Department of Orthopaedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
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14
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Qin D, Yan Y, Hu B, Zhang W, Li H, Li X, Liu S, Dai D, Hu X, Huang X, Zhang L. Wisp2 disruption represses Cxcr4 expression and inhibits BMSCs homing to injured liver. Oncotarget 2017; 8:98823-98836. [PMID: 29228730 PMCID: PMC5716770 DOI: 10.18632/oncotarget.22006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Accepted: 10/02/2017] [Indexed: 11/25/2022] Open
Abstract
Liver regeneration/repair is a compensatory regrowth following acute liver failure, and bone marrow-derived mesenchyme stem cell (BMSC) transplantation is an effective therapy that promotes liver regeneration/repair. Wnt1 inducible signaling pathway protein 2 (Wisp2) is highly expressed in BMSCs, however, its function remains unclear. In this work, we used clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein -9 nuclease (CRISPR/Cas9) genome editing technology to knockdown Wisp2 in BMSCs, and these modified cells were then transplanted into rats which were induced by the 2-AAF/PH. By linking the expression of Cas9 to green fluorescent protein (GFP), we tracked BMSCs in the rats. Disruption of Wisp2 inhibited the homing of BMSCs to injured liver and aggravated liver damage as indicated by remarkably high levels of ALT and AST. Moreover, the key factor in BMSC transplantation, C-X-C chemokine receptor type 4 (Cxcr4), was down-regulated in the Wisp2 depleted BMSCs and had a lower expression in the livers of the corresponding rats. By tracing the GFP marker, more BMSCs were observed to differentiate into CD31 positive endothelial cells in the functional Wisp2 cells but less in the Wisp2 gene disrupted cells. In summary, Wisp2 promotes the homing of BMSCs through Cxcr4 related signaling during liver repair in rats.
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Affiliation(s)
- Dan Qin
- College of Veterinary Medicine, University of Huazhong Agricultural, Wuhan 430070, People's Republic of China
| | - Yi Yan
- College of Veterinary Medicine, University of Huazhong Agricultural, Wuhan 430070, People's Republic of China
| | - Bian Hu
- School of Life Science and Technology, Shanghai Tech University, Pudong New Area, Shanghai 201210, People's Republic of China
| | - Wanpo Zhang
- College of Veterinary Medicine, University of Huazhong Agricultural, Wuhan 430070, People's Republic of China
| | - Hanmin Li
- Hepatic Disease Institute, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430061, People's Republic of China
| | - Xiaodong Li
- Hepatic Disease Institute, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430061, People's Republic of China
| | - Shenghui Liu
- College of Veterinary Medicine, University of Huazhong Agricultural, Wuhan 430070, People's Republic of China
| | - Depeng Dai
- College of Veterinary Medicine, University of Huazhong Agricultural, Wuhan 430070, People's Republic of China
| | - Xiongji Hu
- College of Veterinary Medicine, University of Huazhong Agricultural, Wuhan 430070, People's Republic of China
| | - Xingxu Huang
- School of Life Science and Technology, Shanghai Tech University, Pudong New Area, Shanghai 201210, People's Republic of China
| | - Lisheng Zhang
- College of Veterinary Medicine, University of Huazhong Agricultural, Wuhan 430070, People's Republic of China
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15
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Forostyak S, Sykova E. Neuroprotective Potential of Cell-Based Therapies in ALS: From Bench to Bedside. Front Neurosci 2017; 11:591. [PMID: 29114200 PMCID: PMC5660803 DOI: 10.3389/fnins.2017.00591] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 10/09/2017] [Indexed: 12/12/2022] Open
Abstract
Motor neurons (MN) degeneration is a main feature of amyotrophic lateral sclerosis (ALS), a neurological disorder with a progressive course. The diagnosis of ALS is essentially a clinical one. Most common symptoms include a gradual neurological deterioration that reflect the impairment and subsequent loss of muscle functions. Up-to-date ALS has no therapy that would prevent or cure a disease. Modern therapeutic strategies comprise of neuroprotective treatment focused on antiglutamatergic, antioxidant, antiapoptotic, and anti-inflammatory molecules. Stem cells application and gene therapy has provided researchers with a powerful tool for discovery of new mechanisms and therapeutic agents, as well as opened new perspectives for patients and family members. Here, we review latest progress made in basic, translational and clinical stem cell research related to the ALS. We overviewed results of preclinical and clinical studies employing cell-based therapy to treat neurodegenerative disorders. A special focus has been made on the neuroprotective properties of adult mesenchymal stromal cells (MSC) application into ALS patients. Finally, we overviewed latest progress in the field of embryonic and induced pluripotent stem cells used for the modeling and application during neurodegeneration in general and in ALS in particular.
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Affiliation(s)
- Serhiy Forostyak
- Centre of Reconstructive Neuroscience, Institute of Experimental Medicine (ASCR), Czech Academy of Sciences, Prague, Czechia.,Department of Neuroscience, 2nd Faculty of Medicine, Charles University, Prague, Czechia
| | - Eva Sykova
- Department of Neuroscience, 2nd Faculty of Medicine, Charles University, Prague, Czechia.,Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
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16
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Kumar A, Midha N, Mohanty S, Chohan A, Seth T, Gogia V, Gupta S. Evaluating role of bone marrow-derived stem cells in dry age-related macular degeneration using multifocal electroretinogram and fundus autofluorescence imaging. Int J Ophthalmol 2017; 10:1552-1558. [PMID: 29062775 DOI: 10.18240/ijo.2017.10.12] [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] [Received: 07/27/2016] [Accepted: 09/20/2017] [Indexed: 02/01/2023] Open
Abstract
AIM To evaluate the role of bone marrow-derived stem cells in the treatment of advanced dry age-related macular degeneration (AMD) using multifocal electroretinogram (mf-ERG) and fundus autofluorescence imaging. METHODS Thirty patients (60 eyes) with bilateral central geographic atrophy (GA) were recruited. Worse eye of each patient received autologous bone marrow-derived hematopoietic stem cells (BM-HSCs) (group 1) and the fellow eye with better visual acuity served as control (group 2). The effect of stem cell therapy was determined in terms of visual acuity, amplitude and implicit time in mf-ERG and size of GA on fundus autofluorescence imaging. These tests were performed at presentation and first, third and sixth month follow up. Adverse events (if any) were also monitored. RESULTS At 6mo follow-up there was no statistically significant improvement in median logMAR best corrected visual acuity (BCVA) in either group. Mf-ERG revealed significant improvement in amplitude and implicit time in the intervention group. A significant decrease was also noted in greatest linear dimension (GLD) of GA in the eyes receiving stem cells [6.78±2.60 mm at baseline to 6.56±2.59 mm at 6mo (P=0.021)]. However, no such improvement was noted in the control group. CONCLUSION Electrophysiological and anatomical improvement in the intervention group sheds light on the therapeutic role of BM-HSCs. Further studies are required to determine the stage of disease at which the maximal benefit can be achieved and to standardize the dose and frequency of stem cell injection.
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Affiliation(s)
- Atul Kumar
- Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Neha Midha
- Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Sujata Mohanty
- Stem Cell Facility, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Annu Chohan
- Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Tulika Seth
- Department of Hematology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Varun Gogia
- Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Shikha Gupta
- Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi 110029, India
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17
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Long bone mesenchymal stem cells (Lb-MSCs): clinically reliable cells for osteo-diseases. Cell Tissue Bank 2017; 18:489-500. [DOI: 10.1007/s10561-017-9652-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Accepted: 08/08/2017] [Indexed: 01/24/2023]
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18
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Yoon D, Kim H, Lee E, Park MH, Chung S, Jeon H, Ahn CH, Lee K. Study on chemotaxis and chemokinesis of bone marrow-derived mesenchymal stem cells in hydrogel-based 3D microfluidic devices. Biomater Res 2016; 20:25. [PMID: 27489724 PMCID: PMC4971648 DOI: 10.1186/s40824-016-0070-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 07/15/2016] [Indexed: 12/23/2022] Open
Abstract
Background Controlling the fate of mesenchymal stems cells (MSCs) including proliferation, migration and differentiation has recently been studied by many researchers in the tissue engineering field. Especially, recruitment of stem cells to injury sites is the first and crucial step in tissue regeneration. Although significant progress has been made in the chemotactic migration of MSCs, MSC migration in three dimensional environments remains largely unknown. We developed a 3D hydrogel-based microfluidic-device to study the migration behavior of human MSCs in the presence of stromal-cell derived factor-1α (SDF-1α), interleukin 8 (IL-8) and Substance P (SP) which have been utilized as chemoattractant candidates of human mesenchymal stem cells (hMSCs). Results We systematically investigated the chemotactic migration behaviors of hMSCs and their responses to SDF-1α, IL-8, and SP. SDF-1α was shown to be the most fascinating chemoattractant candidate among those factors at a certain time point. We also found that each chemokine showed different chemoattractant abilities according to their concentration. In the case of SP, this factor showed chemokinesis not chemotaxis. Especially at a 7–8 × 10−8 M concentration range, the chemokinesis ability driven by SP was further increased. The data suggest that some factors at the optimal concentration exhibit chemokinesis or chemotaxis in a 3D hydrogel-based microfluidic device. Conclusion In this study on chemotaxis and chemokinesis of hMSCs, the system parameters such as chemokine concentration, system stability, and 2D or 3D microenvironment are critically important to obtain meaningful results.
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Affiliation(s)
- Dayoung Yoon
- Center for Biomaterials, Korea Institute of Science and Technology, Seoul, Republic of Korea ; Research Institute of Advanced Materials (RIAM), Department of Materials Science and Engineering, Seoul National University, Seoul, Republic of Korea
| | - Hyerim Kim
- Program in Nanoscience and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
| | - Eojin Lee
- Center for Biomaterials, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Min Hee Park
- Center for Biomaterials, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Seok Chung
- School of Mechanical Engineering, Korea University, Seoul, Republic of Korea
| | - Hojeong Jeon
- Center for Biomaterials, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Cheol-Hee Ahn
- Research Institute of Advanced Materials (RIAM), Department of Materials Science and Engineering, Seoul National University, Seoul, Republic of Korea
| | - Kangwon Lee
- Program in Nanoscience and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea ; Advanced Institutes of Convergence Technology, Gyeonggi-do, Republic of Korea
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19
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Therapy Effects of Bone Marrow Stromal Cells on Ischemic Stroke. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:7682960. [PMID: 27069533 PMCID: PMC4812472 DOI: 10.1155/2016/7682960] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 02/25/2016] [Indexed: 01/01/2023]
Abstract
Stroke is the second most common cause of death and major cause of disability worldwide. Recently, bone marrow stromal cells (BMSCs) have been shown to improve functional outcome after stroke. In this review, we will focus on the protective effects of BMSCs on ischemic brain and the relative molecular mechanisms underlying the protective effects of BMSCs on stroke.
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20
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Hua P, Liu JY, Tao J, Yang SR. Application and Progress of Combined Mesenchymal Stem Cell Transplantation in the Treatment of Ischemic Cardiomyopathy. BIOMED RESEARCH INTERNATIONAL 2015; 2015:568502. [PMID: 26295041 PMCID: PMC4532814 DOI: 10.1155/2015/568502] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 06/07/2015] [Indexed: 11/29/2022]
Abstract
Treatment of ischemic cardiomyopathy caused by myocardial infarction (MI) using mesenchymal stem cell (MSC) transplantation is a widely researched field, with promising clinical application. However, the low survival rate of transplanted cells has a severe impact on treatment outcome. Currently, research is focused on investigating the strategy of combining genetic engineering, tissue engineering materials, and drug/hypoxia preconditioning to improve ischemic cardiomyopathy treatment outcome using MSC transplantation treatment (MSCTT). This review discusses the application and progress of these techniques.
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Affiliation(s)
- Ping Hua
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Jian-Yang Liu
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Jun Tao
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Song-Ran Yang
- Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, UK
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21
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Is reduction of tumor burden sufficient for the 21st century? Cancer Lett 2015; 356:149-55. [PMID: 24632530 DOI: 10.1016/j.canlet.2014.03.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 02/11/2014] [Accepted: 03/04/2014] [Indexed: 12/21/2022]
Abstract
Currently, animal models are used to test the efficacy of tumor treatment. A significant reduction of tumor mass is lauded as great improvement. As we begin the 21st century, one wonders if this is sufficient and acceptable for cancer treatment. Although the presence of cancer stem cell (CSCs) is not a new phenomenon, their role in the initiation of the tumor for clinical resurgence is mostly ignored when testing drugs. The current treatment then poses a major limitation to aggressively target the cells most responsible for tumor initiation and resurgence. The review does not trivialize the problem since it is acknowledged that the tumors and cells within the tissue microenvironment would interact through complex mechanisms. It is quite possible that the interaction by CSCs and the microenvironment will vary, depending on the tissue, e.g., bone marrow versus brain. Research studies are needed to investigate if CSCs from the same organ differ after migrating to other tissues. If so, this will pose an economic dilemma for targeted drug development. It will not be feasible to develop drugs for each organ. Besides, the cost, there could be problems to effectively deliver the drugs to all organs, problems to assess drug distribution to particular tissues and toxicity for specific drugs. If multiple drugs are required to eradicate CSCs in different tissues, there is a problem of possible untoward effect for the simultaneous delivery of multiple drugs to a single cancer patient. As new drugs are developed, the investigators will need to pay attention for dedifferentiation of non-CSCs to CSCs. The metabolic pathways will have to be given equal attention as the stem cells genes since their pathways might show major differences rather than the stem cells genes, which are shared by the normal stem cells.
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22
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Sarmento CAP, Rodrigues MN, Bocabello RZ, Mess AM, Miglino MA. Pilot study: bone marrow stem cells as a treatment for dogs with chronic spinal cord injury. Regen Med Res 2014; 2:9. [PMID: 25984337 PMCID: PMC4422475 DOI: 10.1186/2050-490x-2-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 10/15/2014] [Indexed: 01/08/2023] Open
Abstract
Background Chronic Spinal Cord injury is a common, severe, and medically untreatable disease. Since the functional outcomes of acute and experimental chronic spinal cord injury have been shown to improve with stem cell therapy, a case study was conducted to test if the application of stem cell also regenerates chronic SCI dysfunction. Transplantation of foetal bone marrow stem cells was applied in seven dogs with chronic spinal cord injury. Magnetic resonance images and assessments of symptoms according to the Olby scale were used to diagnose the severity of injury. Result All dogs improved locomotor and sensory function when examined 90 days after surgery, and showed increased movement of the hind limbs, and were able to stand upright, as well as to take small steps. Tail tone was observed in seven dogs, pain reflexes and defecation return were observed in five dogs. Conclusion The transplantation of bone marrow stem may be a promising, reliable and safe treatment for chronic spinal cord injury. Electronic supplementary material The online version of this article (doi:10.1186/2050-490X-2-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | - Marcio Nogueira Rodrigues
- School of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo, Brazil ; Cidade Universitaria-Butanta, Av. Prof. Orlando Marques de Paiva, 87, São Paulo, 05508270 Brazil
| | | | - Andrea Maria Mess
- School of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo, Brazil
| | - Maria Angelica Miglino
- School of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo, Brazil
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23
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Li Y, Xing W, He YZ, Chen S, Rhodes SD, Yuan J, Zhou Y, Shi J, Bai J, Zhang FK, Yuan WP, Cheng T, Xu MJ, Yang FC. Interleukin 8/KC enhances G-CSF induced hematopoietic stem/progenitor cell mobilization in Fancg deficient mice. Stem Cell Investig 2014; 1:19. [PMID: 27358865 DOI: 10.3978/j.issn.2306-9759.2014.10.02] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 10/19/2014] [Indexed: 01/21/2023]
Abstract
BACKGROUND Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by a progressive bone marrow aplasia, chromosomal instability, and acquisition of malignancies. Successful hematopoietic cell transplantation (HCT) for FA patients is challenging due to hypersensitivity to DNA alkylating agents and irradiation of FA patients. Early mobilization of autologous stem cells from the bone marrow has been thought to be ideal prior to the onset of bone marrow failure, which often occurs during childhood. However, the markedly decreased response of FA hematopoietic stem cells to granulocyte colony-stimulating factor (G-CSF) is circumventive of this autologous HCT approach. To-date, the mechanism for defective stem cell mobilization in G-CSF treated FA patients remains unclear. METHODS Fancg heterozygous (Fancg (+/-)) mice utilized in these studies. Student's t-test and one-way ANOVA were used to evaluate statistical differences between WT and Fancg (-/-) cells. Statistical significance was defined as P values less than 0.05. RESULTS Fancg deficient (Fancg (-/-)) mesenchymal stem/progenitor cells (MSPCs) produce significant lower levels of KC, an interleukin-8 (IL-8) related chemoattractant protein in rodents, as compared to wild type cells. Combinatorial administration of KC and G-CSF significantly increased the mobilization of hematopoietic stem/progenitor cells (HSPCs) in Fancg (-/-) mice. CONCLUSIONS In summary, our results suggest that KC/IL-8 could be proved useful in the synergistic mobilization of FA HSPCs in combination with G-CSF.
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Affiliation(s)
- Yan Li
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Wen Xing
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Yong-Zheng He
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Shi Chen
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Steven D Rhodes
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jin Yuan
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Yuan Zhou
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jun Shi
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jie Bai
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Feng-Kui Zhang
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Wei-Ping Yuan
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Tao Cheng
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Ming-Jiang Xu
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Feng-Chun Yang
- 1 Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA ; 2 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China ; 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Krüger K, Pilat C, Schild M, Lindner N, Frech T, Muders K, Mooren FC. Progenitor cell mobilization after exercise is related to systemic levels of G-CSF and muscle damage. Scand J Med Sci Sports 2014; 25:e283-91. [PMID: 25264280 DOI: 10.1111/sms.12320] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2014] [Indexed: 01/05/2023]
Abstract
Different types of exercise are characterized by the ability to induce specific physiological stimuli that might be able to induce the mobilization of progenitor cells. The aim of the current study was to investigate the mobilization of hematopoietic progenitor cells (HPCs) and endothelial progenitor cells (EPCs) in response to endurance, resistance, and eccentric endurance exercise and their relation to markers of muscle damage and inflammation. Healthy male subjects performed acute bouts of either endurance exercise, resistance exercise, or eccentric endurance exercise. Numbers of progenitor cells and several markers of muscle damage and inflammation were determined. Although the endurance exercise was followed by an immediate and short increase of both HPCs and EPCs, the eccentric exercise evoked a long lasting increase up to 24 h for HPCs and 48 h for EPCs (P < 0.05). After resistance exercise, an increase of HPCs was only found 3 h after exercise (P < 0.05). A correlation was found between mobilized progenitor cells and systemic levels of granulocyte colony-stimulating factor (G-CSF) levels (r = 0.54 and r = 0.51, P < 0.05) as well as for HPCs and creatine kinase levels (r = 0.57, P < 0.05). These results suggest that mobilization of progenitor cells is related to the type of exercise and possibly mediated by G-CSF and muscle damage.
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Affiliation(s)
- K Krüger
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
| | - C Pilat
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
| | - M Schild
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
| | - N Lindner
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
| | - T Frech
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
| | - K Muders
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
| | - F C Mooren
- Department of Sports Medicine, Institute of Sports Sciences, Justus-Liebig-University, Giessen, Germany
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Atashi F, Jaconi MEE, Pittet-Cuénod B, Modarressi A. Autologous platelet-rich plasma: a biological supplement to enhance adipose-derived mesenchymal stem cell expansion. Tissue Eng Part C Methods 2014; 21:253-62. [PMID: 25025830 DOI: 10.1089/ten.tec.2014.0206] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Currently the use of non-autologous cell culture media (e.g., animal-derived or allogeneic serum) for clinical applications of mesenchymal stem cells (MSCs) is criticized by regulatory agencies. Autologous platelet-rich plasma (PRP) is proposed as a safer alternative medium supplement for adipose-derived mesenchymal stem cells (AT-MSC) culture. To study its efficiency on cell proliferation, AT-MSCs were cultured for 10 days in media supplemented with different concentrations of autologous non-activated PRP (nPRP) or thrombin-activated PRP (tPRP) (1-60%). AT-MSC proliferation, cell phenotype, multipotency capacity, and chromosome stability were assessed and compared to AT-MSCs expanded in a classical medium supplemented with 10% of fetal bovine serum (FBS). Culture media supplemented with nPRP showed dose-dependent higher AT-MSC proliferation than did FBS or tPRP. Twenty percent nPRP was the most effective concentration to promote cell proliferation. This condition increased 13.9 times greater AT-MSC number in comparison to culture with FBS, without changing the AT-MSC phenotype, differentiation capacity, and chromosome status. We concluded that 20% autologous nPRP is a safe, efficient, and cost-effective supplement for AT-MSC expansion. It should be considered as an alternative to FBS or other nonautologous blood derivatives. It could serve as a potent substitute for the validation of future clinical protocols as it respects good manufacturing practices and regulatory agencies' standards.
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Affiliation(s)
- Fatemeh Atashi
- 1 Department of Plastic, Reconstructive and Aesthetic Surgery, University Hospitals of Geneva (HUG) , Faculty of Medicine, Geneva University, Geneva, Switzerland
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26
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Sun Z, Wang C, Shi C, Sun F, Xu X, Qian W, Nie S, Han X. Activated Wnt signaling induces myofibroblast differentiation of mesenchymal stem cells, contributing to pulmonary fibrosis. Int J Mol Med 2014; 33:1097-109. [PMID: 24573542 PMCID: PMC4020487 DOI: 10.3892/ijmm.2014.1672] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Accepted: 01/29/2014] [Indexed: 01/11/2023] Open
Abstract
Acute lung injury may lead to fibrogenesis. However, no treatment is currently available. This study was conducted to determine the effects of bone marrow-derived mesenchymal stem cells (MSCs) in a model of HCl-induced acute lung injury in Sprague-Dawley (SD) rats. Stromal cell-derived factor (SDF)-1 and its receptor CXC chemokine receptor (CXCR)4 have been shown to participate in mobilizing MSCs. Adenovirus carrying the CXCR4 gene was used to transfect MSCs in order to increase the engraftment numbers of MSCs at injured sites. Histological examination data demonstrated that the engraftment of MSCs did not attenuate lung injury and pulmonary fibrosis. The results showed that engraftment of MSCs almost differentiated into myofibroblasts, but rarely differentiated into lung epithelial cells. Additionally, it was demonstrated that activated canonical Wnt/β-catenin signaling in injured lung tissue regulated the myofibroblast differentiation of MSCs in vivo. The in vitro study results demonstrated that activation of the Wnt/β-catenin signaling stimulated MSCs to express myofibroblast markers; however, this process was attenuated by Wnt antagonist DKK1. Therefore, the results demonstrated that the aberrant activation of Wnt signaling induces the myofibroblast differentiation of engrafted MSCs, thus contributing to pulmonary fibrosis following lung injury.
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Affiliation(s)
- Zhaorui Sun
- Immunology and Reproductive Biology Laboratory, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Cong Wang
- Immunology and Reproductive Biology Laboratory, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Chaowen Shi
- Immunology and Reproductive Biology Laboratory, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Fangfang Sun
- Immunology and Reproductive Biology Laboratory, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Xiaomeng Xu
- Immunology and Reproductive Biology Laboratory, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Weiping Qian
- State Key Laboratory of Bioelectronics, Southeast University, Nanjing, Jiangsu 210093, P.R. China
| | - Shinan Nie
- Department of Emergency, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Xiaodong Han
- Immunology and Reproductive Biology Laboratory, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
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van Vliet P, Sluijter JPG, Doevendans PA, Goumans MJ. Isolation and expansion of resident cardiac progenitor cells. Expert Rev Cardiovasc Ther 2014; 5:33-43. [PMID: 17187455 DOI: 10.1586/14779072.5.1.33] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
After myocardial infarction, loss of viable cardiomyocytes severely impairs cardiac function. Recently, stem cell transplantation has been put forward as a promising approach to repair the damaged heart. Although several clinical trials have already been performed, the dominant beneficial effects are probably due to neoangiogenesis and arteriogenesis. However, replacement of cardiomyocytes is vital to improve cardiac function in the long term. Stem cells and progenitor cells, with the capacity to differentiate into cardiomyocytes, have been described in both embryonic and adult tissues. Upon stimulation, cardiac progenitor cells proliferate and differentiate into cardiomyocytes, vascular smooth muscle cells, and endothelial cells. Currently however, high proliferation rates and differentiation of cardiac progenitor cells beyond the fetal stage have not yet been achieved. Full differentiation into adult cardiomyocytes in vitro and in vivo might be important for efficient integration with the host environment and therefore more research is needed to study factors that influence proliferation and differentiation. Here we will discuss the isolation of cardiac progenitor cells, their potential to differentiate into various cell types needed for cardiac repair, the possible mechanisms behind these events, and how these cells may be implemented in future clinical settings.
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Affiliation(s)
- Patrick van Vliet
- The Interuniversity Cardiology Institute of The Netherlands, Utrecht, The Netherlands.
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Aggarwal R, Pompili VJ, Das H. Generation of osteoporosis in immune-compromised mice for stem cell therapy. Methods Mol Biol 2014; 1213:209-214. [PMID: 25173385 DOI: 10.1007/978-1-4939-1453-1_17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
To evaluate therapeutic efficacy and to investigate involved molecular mechanisms of cell-based therapy in osteoporosis, the generation of a clinically relevant model is critically important. Herein, we describe detailed methods in generation of an immune-deficient osteoporotic murine model, and application of human umbilical cord blood-derived stem cells to assess their therapeutic efficacy.
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Affiliation(s)
- Reeva Aggarwal
- Cardiovascular Stem Cell Laboratories, The Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center at The Ohio State University, 460 W. 12th Avenue, BRT 394, Columbus, OH, 43210, USA
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Chen J, Shehadah A, Pal A, Zacharek A, Cui X, Cui Y, Roberts C, Lu M, Zeitlin A, Hariri R, Chopp M. Neuroprotective effect of human placenta-derived cell treatment of stroke in rats. Cell Transplant 2013; 22:871-9. [PMID: 22469567 DOI: 10.3727/096368911x637380] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
UNLABELLED Human placenta-derived adherent (PDA001) cells are mesenchymal-like stem cells isolated from postpartum placenta. In this study, we tested whether intravenously infused PDA001 improves neurological functional recovery after stroke in rats. In addition, potential mechanisms underlying the PDA001-induced neuroprotective effect were investigated. Young adult male rats (2–3 months) were subjected to 2 h of middle cerebral artery occlusion (MCAo) and treated with PDA001 (4x10(6)) or vehicle controls [dextran vehicle or phosphate buffer saline (PBS)] via intravenous (IV) administration initiated at 4 h after MCAo. A battery of functional tests and measurements of lesion volume and apoptotic cells were performed. Immunostaining and ELISA assays for vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) and brain derived neurotrophic factor (BDNF) were performed in the ischemic brain to test the potential mechanisms underlying the neuroprotective effects of PDA001 cell treatment of stroke. PDA001 cell treatment at 4 h post stroke significantly improved functional outcome and significantly decreased lesion volume, TUNEL, and cleaved caspase 3-positive cell number in the ischemic brain, compared to MCAo-vehicle and MCAo-PBS control. Treatment of stroke with PDA001 cells also significantly increased HGF and VEGF expression in the ischemic border zone (IBZ) compared to controls. Using ELISA assays, treatment of stroke with PDA001 cells significantly increased VEGF, HGF, and BDNF levels in the ischemic brain compared to controls. CONCLUSION When administered intravenously at 4 h after MCAo, PDA001 cells promoted neuroprotective effects. These effects induced by PDA001 cell treatment may be related to the increase of VEGF, HGF, and BDNF expression,and a decrease of apoptosis. PDA001 cells may provide a viable cell source to treat stroke.
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Affiliation(s)
- Jieli Chen
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.
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30
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The role of mesenchymal stromal cells in spinal cord injury, regenerative medicine and possible clinical applications. Biochimie 2013; 95:2257-70. [DOI: 10.1016/j.biochi.2013.08.004] [Citation(s) in RCA: 101] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Accepted: 08/05/2013] [Indexed: 12/13/2022]
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Intramuscular transplantation and survival of freshly isolated bone marrow cells following skeletal muscle ischemia-reperfusion injury. J Trauma Acute Care Surg 2013; 75:S142-9. [PMID: 23883899 DOI: 10.1097/ta.0b013e31829ac1fa] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Delayed treatment cellular therapies offer an attractive means to treat extremity injuries involving acute skeletal muscle ischemia-reperfusion injury (I/R). Bone marrow is a rich source of stem and progenitor cells with the potential to improve skeletal muscle regeneration. The extent to which bone marrow cells (BMCs) may be useful for I/R is not known. The purposes of this study were twofold: (1) to evaluate BMC survival following intramuscular injection 0, 2, 7, and 14 days after injury and (2) to determine whether BMCs improve functional recovery following I/R. METHODS Magnetic-activated cell sorting was used to isolate lineage-negative (Lin⁻) BMCs and enrich for stem and progenitor cells. To evaluate in vivo cell survival following I/R, Lin⁻ BMCs were injected intramuscularly 0, 2, 7, and 14 days after I/R, and bioluminescent imaging was performed for up to 28 days after cell injections. To assess their ability to improve muscle regeneration, intramuscular injections were performed 2 days after injury, and in vivo muscle function was assessed 14 days later. RESULTS Lin⁻ BMCs survived throughout the study period regardless of the timing of delivery. Intramuscular injection of Lin⁻ BMCs did not improve maximal isometric torque (300 Hz); however, both saline-injected and Lin⁻ BMC-injected muscles exhibited an increase in the twitch-tetanus ratio, suggesting that damage incurred with the intramuscular injections may have had deleterious consequences for functional recovery. CONCLUSION Although BMCs injected intramuscularly survived cell transplantation, they failed to improve muscle function following I/R. The ability of BMCs to persist in injured muscle following I/R lends to the possibility that with further development, their full potential can be realized.
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Khan M, Ali F, Mohsin S, Akhtar S, Mehmood A, Choudhery MS, Khan SN, Riazuddin S. Preconditioning diabetic mesenchymal stem cells with myogenic medium increases their ability to repair diabetic heart. Stem Cell Res Ther 2013; 4:58. [PMID: 23706645 PMCID: PMC3707006 DOI: 10.1186/scrt207] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Revised: 04/21/2013] [Accepted: 05/16/2013] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Mesenchymal stem cells (MSCs) have the potential for treatment of diabetic cardiomyopathy; however, the repair capability of MSCs declines with age and disease. MSCs from diabetic animals exhibit impaired survival, proliferation, and differentiation and therefore require a strategy to improve their function. The aim of the study was to develop a preconditioning strategy to augment the ability of MSCs from diabetes patients to repair the diabetic heart. METHODS Diabetes was induced in C57BL/6 mice (6 to 8 weeks) with streptozotocin injections (55 mg/kg) for 5 consecutive days. MSCs isolated from diabetic animals were preconditioned with medium from cardiomyocytes exposed to oxidative stress and high glucose (HG/H-CCM). RESULTS Gene expression of VEGF, ANG-1, GATA-4, NKx2.5 MEF2c, PCNA, and eNOS was upregulated after preconditioning with HG/H-CCM, as evidenced by reverse transcriptase/polymerase chain reaction (RT-PCR). Concurrently, increased AKT phosphorylation, proliferation, angiogenic ability, and reduced levels of apoptosis were observed in HG/H-CCM-preconditioned diabetic MSCs compared with nontreated controls. HG/H-CCM-preconditioned diabetic-mouse-derived MSCs (dmMSCs) were transplanted in diabetic animals and demonstrated increased homing concomitant with augmented heart function. Gene expression of angiogenic and cardiac markers was significantly upregulated in conjunction with paracrine factors (IGF-1, HGF, SDF-1, FGF-2) and, in addition, reduced fibrosis, apoptosis, and increased angiogenesis was observed in diabetic hearts 4 weeks after transplantation of preconditioned dmMSCs compared with hearts with nontreated diabetic MSCs. CONCLUSIONS Preconditioning with HG/H-CCM enhances survival, proliferation, and the angiogenic ability of dmMSCs, augmenting their ability to improve function in a diabetic heart.
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Affiliation(s)
- Mohsin Khan
- National Center of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Fatima Ali
- National Center of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Sadia Mohsin
- National Center of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Shoaib Akhtar
- National Center of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Azra Mehmood
- National Center of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Mahmood S Choudhery
- National Center of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Shaheen N Khan
- National Center of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Sheikh Riazuddin
- National Center of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
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Profiling and semiquantitative analysis of the cell surface proteome in human mesenchymal stem cells. Anal Bioanal Chem 2013; 405:5501-17. [DOI: 10.1007/s00216-013-6969-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Revised: 03/13/2013] [Accepted: 04/03/2013] [Indexed: 12/20/2022]
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Sykova E, Forostyak S. Stem cells in regenerative medicine. Laser Ther 2013; 22:87-92. [PMID: 24155553 DOI: 10.3136/islsm.22.87] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Accepted: 06/03/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND A number of cardiovascular, neurological, musculoskeletal and other diseases have a limited capacity for repair and only a modest progress has been made in treatment of brain diseases. The discovery of stem cells has opened new possibilities for the treatment of these maladies, and cell therapy now stands at the cutting-edge of modern regenerative medicine and tissue engineering. Experimental data and the first clinical trials employing stem cells have shown their broad therapeutic potential and have brought hope to patients suffering from devastating pathologies of different organs and systems. AIMS Here, we briefly review the main achievements and trends in cell-based therapy, with an emphasis on the main types of stem cells: embryonic, mesenchymal stromal and induced pluripotent cells. DISCUSSION Many questions regarding the application of stem cells remain unanswered, particularly tumorigenicity, immune rejection and danger of gene manipulation. Currently, only MSC seems to be safe and might be considered to be a leading candidate for human application to treat pathologies that affect the cardiovascular, neurological and musculoskeletal systems.
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Affiliation(s)
- Eva Sykova
- Department of Neuroscience, Institute of Experimental Medicine, Academy of Science of the Czech Republic, Videnska 1083, Prague, 14220, Czech Republic ; Department of Neuroscience, 2nd Faculty of Medicine, Charles University, V Uvalu 84, Prague, 15006, Czech Republic
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Abstract
BACKGROUND A number of cardiovascular, neurological, musculoskeletal and other diseases have a limited capacity for repair and only a modest progress has been made in treatment of brain diseases. The discovery of stem cells has opened new possibilities for the treatment of these maladies, and cell therapy now stands at the cutting-edge of modern regenerative medicine and tissue engineering. Experimental data and the first clinical trials employing stem cells have shown their broad therapeutic potential and have brought hope to patients suffering from devastating pathologies of different organs and systems. AIMS Here, we briefly review the main achievements and trends in cell-based therapy, with an emphasis on the main types of stem cells: embryonic, mesenchymal stromal and induced pluripotent cells. DISCUSSION Many questions regarding the application of stem cells remain unanswered, particularly tumorigenicity, immune rejection and danger of gene manipulation. Currently, only MSC seems to be safe and might be considered to be a leading candidate for human application to treat pathologies that affect the cardiovascular, neurological and musculoskeletal systems.
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Affiliation(s)
- Eva Sykova
- Department of Neuroscience, Institute of Experimental Medicine, Academy of Science of the Czech Republic, Videnska 1083, Prague, 14220, Czech Republic ; Department of Neuroscience, 2nd Faculty of Medicine, Charles University, V Uvalu 84, Prague, 15006, Czech Republic
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Zhuo W, Liao L, Fu Y, Xu T, Wu W, Yang S, Tan J. Efficiency of endovenous versus arterial administration of mesenchymal stem cells for ischemia-reperfusion-induced renal dysfunction in rats. Transplant Proc 2013; 45:503-10. [PMID: 23498785 DOI: 10.1016/j.transproceed.2012.07.162] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2012] [Revised: 07/08/2012] [Accepted: 07/19/2012] [Indexed: 01/16/2023]
Abstract
BACKGROUND Ischemia followed by reperfusion leads to acute renal failure in both native kidneys and a renal allograft. Our previous study found that transplantation of mesenchymal stem cells (MSCs) ameliorated ischemia-reperfusion (I/R)-induced kidney dysfunction by increasing the activities of antioxidant enzymes. The purpose of this study was to evaluate whether intra-arterial versus intravenous administration was more effective. METHODS Renal ischemia was induced by clamping the right renal vessels for 60 minutes after removal of the left kidney. MSCs (1 × 10(6)) were administered through either the tail vein (TV) or the renal arter (RA), followed by reperfusion. We evaluated kidney function as well as tissue activities of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px). Histopathologic and immunohistochemical examinations were performed. To tracking MSCs in vivo, they were transfected with firefly luciferase and monomeric red fluorescent protein reporter genes (fluc-mrfp). MSC retention and survival were assessed using bioluminescence imaging. We observed the effects of MSCs (1 × 10(6), 2 × 10(6), and 5 × 10(6)) on IR injury. RESULTS MSC infusion via either the tail vein or the renal artery significantly improved kidney function at days 1, 3, and 5 as indicated by lower urea and creatinine levels compared with vehicle controls (P < .05). I/R induced a reduction in renal tissue SOD activity but GSH-PX was significantly improved by MSCs (P < .05) on day 1. Treatment with MSCs also significantly reduced renal tissue MDA levels that had been otherwise increased by renal I/R injury (P < .05). The above parameters were similar between the TV and the RA groups. Histological examination revealed kidneys from MSC-treated rats to show fairly normal morphology. The percentages of proliferating cell nuclear antigen (PCNA)-positive cells were higher in the MSC groups: 16.83 ± 4.62%, 19.17 ± 6.21%, and 2.17 ± 1.16% for the TV, RA, and control groups, respectively. There was no significant dose-related difference among MSC groups. Bioluminescence imaging demonstrated most MSCs to be lost within 7 days after either intravenous or intra-arterial infusion. CONCLUSIONS MSCs ameliorated I/R-induced acute renal failure in rats with similar efficiency whether infused either through the TV or the RA. There was no dose-dependent responses.
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Affiliation(s)
- W Zhuo
- Organ Transplant Institute, Fuzhou General Hospital, Fuzhou General Hospital of Nanjing Command of PLA, Xiamen University, Fuzhou, China
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Estradiol synthesis and release in cultured female rat bone marrow stem cells. BIOMED RESEARCH INTERNATIONAL 2012; 2013:301540. [PMID: 23484106 PMCID: PMC3591230 DOI: 10.1155/2013/301540] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Revised: 11/21/2012] [Accepted: 11/29/2012] [Indexed: 01/11/2023]
Abstract
Bone marrow stem cells (BMSCs) have the capacity to differentiate into mature cell types of multiple tissues. Thus, they represent an alternative source for organ-specific cell replacement therapy in degenerative diseases. In this study, we demonstrated that female rat BMSCs could differentiate into steroidogenic cells with the capacity for de novo synthesis of Estradiol-17β (E2) under high glucose culture conditions with or without retinoic acid (RA). The cultured BMSCs could express the mRNA and protein for P450arom, the enzyme responsible for estrogen biosynthesis. Moreover, radioimmunoassay revealed that BMSCs cultured in the present culture system produced and secreted significant amounts of testosterone, androstenedione, and E2. In addition, RA promoted E2 secretion but did not affect the levels of androgen. These results indicate that BMSCs can synthesize and release E2 and may contribute to autologous transplantation therapy for estrogen deficiency.
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Park C, Lee JY, Yoon YS. Role of bone marrow-derived lymphatic endothelial progenitor cells for lymphatic neovascularization. Trends Cardiovasc Med 2012; 21:135-40. [PMID: 22732548 DOI: 10.1016/j.tcm.2012.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The lymphatic vasculature plays a pivotal role in maintaining tissue fluid homeostasis, immune surveillance, and lipid uptake in the gastrointestinal organs. Therefore, impaired function of the lymphatic vessels caused by genetic defects, infection, trauma, or surgery leads to the abnormal accrual of lymph fluid in the tissue and culminates in the swelling of affected tissues, known as lymphedema. Lymphedema causes impaired wound healing, compromised immune defense, and, in rare case, lymphangiosarcoma. Although millions of people suffer from lymphedema worldwide, no effective therapy is currently available. In addition, recent advances in cancer biology have disclosed an indispensable function of the lymphatic vessel in tumor growth and metastasis. Therefore, understanding the detailed mechanisms governing lymphatic vessel formation and function in pathophysiologic conditions is essential to prevent or treat these diseases. We review the developmental processes of the lymphatic vessels and postnatal lymphatic neovascularization, focusing on the role of recently identified bone marrow-derived podoplanin-expressing (podoplanin(+)) cells as lymphatic endothelial progenitor cells.
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Affiliation(s)
- Changwon Park
- Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA
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Li ZM, Zhang ZT, Guo CJ, Geng FY, Qiang F, Wang LX. Autologous bone marrow mononuclear cell implantation for intracerebral hemorrhage-a prospective clinical observation. Clin Neurol Neurosurg 2012; 115:72-6. [PMID: 22657095 DOI: 10.1016/j.clineuro.2012.04.030] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Revised: 04/06/2012] [Accepted: 04/28/2012] [Indexed: 01/01/2023]
Abstract
BACKGROUND This study was designed to assess the clinical effect of bone marrow mononuclear cells including mesenchymal stem cell (MSCs) in patients with intracerebral hemorrhage (ICH). METHODS One hundred patients were divided into a study (n=60) or a control group (n=40). Bone marrow mononuclear cells from the same patient were injected to the perihemorrhage area in the base ganglia through an intracranial drainage tube 5.9 days after ICH. National Institute Stroke Scale (NIHSSS) and Barthel index was used to assess neurologic impairment and daily activities, respectively, before and 6 months after intervention. RESULTS Six months after implantation, the NIHSS score in the study group was lower than in the control group (10.09 ± 8.86 vs 14.35 ± 10.14, P<0.01), whereas the Barthel scores were higher (57.39 ± 23.51 vs 46.90 ± 20.29, P<0.01). Neurological and functional improvement was observed in 52 (86.7%) of the study group patients, and in 17 (42.5%) of the control group patients (P=0.001). No allergic or other adverse effects were observed in the study group. CONCLUSION Autologous bone marrow mononuclear cell implantation reduced neurological impairment and improved activities of daily living in a selected group of ICH patients. Further studies are required to ascertain the long-term safety and efficacy of this treatment.
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Affiliation(s)
- Zhong-Min Li
- Department of Neurosurgery, Liaocheng People's Hospital of Taishan Medical University, Liaocheng, Shandong 252000, PR China.
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Friedlander M. Advances in treatment and management: immunologic and cell-based regenerative therapies. Invest Ophthalmol Vis Sci 2012; 53:2511-4. [PMID: 22562853 DOI: 10.1167/iovs.12-9483p] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Martin Friedlander
- Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
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Lai VK, Afzal MR, Ashraf M, Jiang S, Haider HK. Non-hypoxic stabilization of HIF-Iα during coordinated interaction between Akt and angiopoietin-1 enhances endothelial commitment of bone marrow stem cells. J Mol Med (Berl) 2012; 90:719-30. [PMID: 22237590 DOI: 10.1007/s00109-011-0852-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 12/16/2011] [Accepted: 12/23/2011] [Indexed: 10/14/2022]
Abstract
We previously reported that mesenchymal stem cells (MSC) co-expressing Akt and angiopoietin-1 (Ang-1) preserved infarcted heart function via angiomyogenesis. The present study determined the mechanism of co-overexpression of Akt and Ang-1 in promoting endothelial commitment of MSC. The cells were transduced with vectors encoding for Akt ((Akt)MSC), Ang-1 ((Ang-1)MSC), and both Akt and Ang-1 ((AA)MSC) using Empty vector transduced MSC ((Emp)MSC) as control. Molecular studies indicated a coordinated interaction between Akt and Ang-1 in (AA)MSC and led to non-hypoxic stabilization of hypoxia inducible factor-1α (HIF-Iα) which accentuated under 4-h anoxia. We also observed HIF-Iα dependent induction of hemeoxygenase-1, endothelial specific markers and VEGF in (AA)MSC. Vascular commitment of (AA)MSC was confirmed by immunostaining, Western blotting and flow cytometry for endothelial specific early and late markers including Flt1, Flk1, Tie2, VCAM-1, and von Willebrand Factor-VIII (vWF-VIII) in HIF-Iα dependent fashion besides exhibiting higher emigrational activity and angiogenesis in vitro. (AA)MSC transplanted into rat model of myocardial infarction showed higher Flk1 and Flt1 positivity and also promoted intrinsic Flk1(+) and Flt1(+) cell mobilization into the infarcted heart. Given the ease of availability of MSC and simplicity of approach to co-overexpress Ang-1 and Akt to enhance their endothelial commitment, the strategy will be significant for cellular angiogenesis to treat ischemic heart.
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Affiliation(s)
- Vien Khach Lai
- Department of Pathology, University of Cincinnati Medical Center, 231-Albert Sabin Way, Cincinnati, OH 45267-0529, USA
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Akahane M, Ueha T, Shimizu T, Inagaki Y, Kido A, Imamura T, Kawate K, Tanaka Y. Increased osteogenesis with hydroxyapatite constructs combined with serially-passaged bone marrow-derived mesenchymal stem cells. ACTA ACUST UNITED AC 2012. [DOI: 10.4236/scd.2012.24018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Liu Z, Huang D, Zhang M, Chen Z, Jin J, Huang S, Zhang Z, Wang Z, Chen L, Chen L, Xu Y. Cocaine- and amphetamine-regulated transcript promotes the differentiation of mouse bone marrow-derived mesenchymal stem cells into neural cells. BMC Neurosci 2011; 12:67. [PMID: 21756347 PMCID: PMC3199873 DOI: 10.1186/1471-2202-12-67] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Accepted: 07/14/2011] [Indexed: 01/01/2023] Open
Abstract
Background Neural tissue has limited potential to self-renew after neurological damage. Cell therapy using BM-MSCs (bone marrow mesenchymal stromal cells) seems like a promising approach for the treatment of neurological diseases. However, the neural differentiation of stem cells influenced by massive factors and interactions is not well studied at present. Results In this work, we isolated and identified MSCs from mouse bone marrow. Co-cultured with CART (0.4 nM) for six days, BM-MSCs were differentiated into neuron-like cells by the observation of optical microscopy. Immunofluorescence demonstrated that the differentiated BM-MSCs expressed neural specific markers including MAP-2, Nestin, NeuN and GFAP. In addition, NeuN positive cells could co-localize with TH or ChAT by double-labled immunofluorescence and Nissl bodies were found in several differentiated cells by Nissl stain. Furthermore, BDNF and NGF were increased by CART using RT-PCR. Conclusion This study demonstrated that CART could promote the differentiation of BM-MSCs into neural cells through increasing neurofactors, including BNDF and NGF. Combined application of CART and BM-MSCs may be a promising cell-based therapy for neurological diseases.
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Affiliation(s)
- Zhuo Liu
- Department of Neurology, Drum Tower Hospital of Nanjing Medical University, 321 Zhongshan Road, Nanjing, Jiangsu 210008, P.R. China
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Francipane MG, Cervello M, Vizzini GB, Pietrosi G, Montalto G. Management of Liver Failure: From Transplantation to Cell-Based Therapy. CELL MEDICINE 2011; 2:9-25. [PMID: 26998399 DOI: 10.3727/215517911x575993] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The severe shortage of deceased donor organs has driven a search for alternative methods of treating liver failure. In this context, cell-based regenerative medicine is emerging as a promising interdisciplinary field of tissue repair and restoration, able to contribute to improving health in a minimally invasive fashion. Several cell types have allowed long-term survival in experimental models of liver injury, but their therapeutic potential in humans should be regarded with deep caution, because few clinical trials are currently available and the number of patients enrolled so far is too small to assess benefits versus risks. This review summarizes the current literature on the physiological role of endogenous stem cells in liver regeneration and on the therapeutic benefits of exogenous stem cell administration with specific emphasis on the potential clinical uses of mesenchymal stem cells. Moreover, critical points that still need clarification, such as the exact identity of the stem-like cell population exerting the beneficial effects, as well as the limitations of stem cell-based therapies, are discussed.
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Affiliation(s)
- Maria Giovanna Francipane
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy," National Research Council (CNR), Palermo, Italy; †Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy
| | - Melchiorre Cervello
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy," National Research Council (CNR) , Palermo , Italy
| | - Giovanni Battista Vizzini
- ‡ Istituto Mediterraneo Trapianti e Terapie ad Alta Specializzazione, University of Pittsburgh Medical Center in Italy , Palermo , Italy
| | - Giada Pietrosi
- ‡ Istituto Mediterraneo Trapianti e Terapie ad Alta Specializzazione, University of Pittsburgh Medical Center in Italy , Palermo , Italy
| | - Giuseppe Montalto
- † Department of Internal Medicine and Specialties, University of Palermo , Palermo , Italy
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Yu T, Lan SY, Wu B, Pan QH, Shi L, Huang KH, Lin Y, Chen QK. Musashi1 and hairy and enhancer of split 1 high expression cells derived from embryonic stem cells enhance the repair of small-intestinal injury in the mouse. Dig Dis Sci 2011; 56:1354-1368. [PMID: 21221806 DOI: 10.1007/s10620-010-1441-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2010] [Accepted: 09/19/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND Embryonic stem cells have great plasticity. In this study, we repaired impaired small intestine by transplanting putative intestinal epithelial stem cells (Musashi1 and hairy and enhancer of split 1 high expression cells) derived from embryonic stem cells. METHODS The differentiation of definitive endoderm in embryoid bodies, derived from male ES-E14TG2a cells by the hanging-drop method, was monitored to define a time point for maximal induction of putative intestinal epithelial stem cells by epidermal growth factor. Furthermore, to evaluate the regenerative potential of intestinal epithelium, these putative stem cells were engrafted into NOD/SCID mice and female mice with enteritis. Donor cells were located by SRY DNA in situ hybridization. RESULTS The results revealed that definitive endodermal markers were highly expressed in 5-day embryoid bodies. These embryoid body cells were induced into putative intestinal epithelial stem cells on the 5th day of epidermal growth factor administration. Grafts from these cells consisted of adenoid structures and nonspecific structural cells with strong expression of small-intestinal epithelial cell markers. In situ hybridization revealed that the donor cells could specifically locate in damaged intestinal epithelium, contribute to epithelial structures, and enhance regeneration. CONCLUSIONS In conclusion, the Musashi1 and hairy and enhancer of split 1 high expression cells, derived from mouse embryonic stem cells, locate predominantly in impaired small-intestinal epithelium after transplantation and contribute to epithelial regeneration.
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Affiliation(s)
- Tao Yu
- Department of Gastroenterology, The Second Affiliated Hospital, Sun Yat-Sen University, 107 Yan Jiang Xi Road, 510120, Guangzhou, Guangdong, People's Republic of China
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Guan L, Yu J, Zhong L, Huang B, Luo T, Zhang M, Lin S, Li W, Ge J, Chen X, Liu Q, Zeng MZ, Song X. Biological safety of human skin-derived stem cells after long-term in vitro culture. J Tissue Eng Regen Med 2011; 5:97-103. [DOI: 10.1002/term.290] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Zhuo W, Liao L, Xu T, Wu W, Yang S, Tan J. Mesenchymal Stem Cells Ameliorate Ischemia-Reperfusion-Induced Renal Dysfunction by Improving the Antioxidant/Oxidant Balance in the Ischemic Kidney. Urol Int 2011; 86:191-6. [DOI: 10.1159/000319366] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Accepted: 07/07/2010] [Indexed: 01/22/2023]
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Ding J, Cheng Y, Gao S, Chen J. Effects of nerve growth factor and Noggin-modified bone marrow stromal cells on stroke in rats. J Neurosci Res 2010; 89:222-30. [DOI: 10.1002/jnr.22535] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2010] [Revised: 09/15/2010] [Accepted: 09/30/2010] [Indexed: 01/18/2023]
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Bone marrow stem cell derived paracrine factors for regenerative medicine: current perspectives and therapeutic potential. BONE MARROW RESEARCH 2010; 2011:207326. [PMID: 22046556 PMCID: PMC3195349 DOI: 10.1155/2011/207326] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2010] [Accepted: 10/12/2010] [Indexed: 12/11/2022]
Abstract
During the past several years, there has been intense research in the field of bone marrow-derived stem cell (BMSC) therapy to facilitate its translation into clinical setting. Although a lot has been accomplished, plenty of challenges lie ahead. Furthermore, there is a growing body of evidence showing that administration of BMSC-derived conditioned media (BMSC-CM) can recapitulate the beneficial effects observed after stem cell therapy. BMSCs produce a wide range of cytokines and chemokines that have, until now, shown extensive therapeutic potential. These paracrine mechanisms could be as diverse as stimulating receptor-mediated survival pathways, inducing stem cell homing and differentiation or regulating the anti-inflammatory effects in wounded areas. The current review reflects the rapid shift of interest from BMSC to BMSC-CM to alleviate many logistical and technical issues regarding cell therapy and evaluates its future potential as an effective regenerative therapy.
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