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Yoshizawa T, Lee JW, Hong SM, Jung D, Noë M, Zbijewski W, Kiemen A, Wu PH, Wirtz D, Hruban RH, Wood LD, Oshima K. Three-dimensional analysis of ductular reactions and their correlation with liver regeneration and fibrosis. Virchows Arch 2024; 484:753-763. [PMID: 37704824 DOI: 10.1007/s00428-023-03641-3] [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: 04/18/2023] [Revised: 08/24/2023] [Accepted: 08/30/2023] [Indexed: 09/15/2023]
Abstract
The liver has multiple regeneration modes, including hepatocellular hypertrophy and self-renewal of hepatocytes. When hepatocyte proliferation is impaired, hepatic progenitor cells may proliferate through ductular reaction (DR), differentiate into hepatocytes, and contribute to fibrosis. However, the three-dimensional spatial relationship between DR and regenerating hepatocytes and dynamic changes in DR associated with fibrosis remain poorly understood. Here, we performed three-dimensional (3D) imaging of cleared 42 liver explants with chronic and acute liver diseases and 4 normal livers to visualize DR. In chronic hepatic liver diseases, such as viral hepatitis, steatohepatitis, autoimmune hepatitis, and cryptogenic cirrhosis, the total length and number of branches of DR showed a significant positive correlation. We studied the spatial relationship between DR and GS-expressing cells using glutamine synthetase (GS) and cytokeratin 19 (CK19) as markers of liver regeneration and DR, respectively. The percentage of CK19-positive cells that co-expressed GS was less than 10% in chronic liver diseases. In contrast, nearly one-third of CK19-positive cells co-expressed GS in acute liver diseases, and chronic cholestatic liver diseases, including primary biliary cholangitis and primary sclerosing cholangitis, showed no co-expression. We also found that DR was longer and had more branching in livers with progressive fibrosis compared to those with regressive fibrosis. Our results suggest that DR displays varying degrees of spatial complexity and contribution to liver regeneration. DR may serve as hepatobiliary junctions that maintain continuity between hepatocytes and bile ducts rather than hepatocyte regeneration in chronic liver diseases.
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Affiliation(s)
- Tadashi Yoshizawa
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki Aomori, Japan
| | - Jae W Lee
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Seung-Mo Hong
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - DongJun Jung
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Medicine, Graduate School, University of Ulsan, Seoul, Republic of Korea
| | - Michaël Noë
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Wojciech Zbijewski
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Ashley Kiemen
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Pei-Hsun Wu
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Denis Wirtz
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Ralph H Hruban
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura D Wood
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kiyoko Oshima
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Castro Nava A, Doolaar IC, Labude-Weber N, Malyaran H, Babu S, Chandorkar Y, Di Russo J, Neuss S, De Laporte L. Actuation of Soft Thermoresponsive Hydrogels Mechanically Stimulates Osteogenesis in Human Mesenchymal Stem Cells without Biochemical Factors. ACS APPLIED MATERIALS & INTERFACES 2024; 16:30-43. [PMID: 38150508 PMCID: PMC10789260 DOI: 10.1021/acsami.3c11808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 12/29/2023]
Abstract
Mesenchymal stem cells (MSCs) have the potential to differentiate into multiple lineages and can be harvested relatively easily from adults, making them a promising cell source for regenerative therapies. While it is well-known how to consistently differentiate MSCs into adipose, chondrogenic, and osteogenic lineages by treatment with biochemical factors, the number of studies exploring how to achieve this with mechanical signals is limited. A relatively unexplored area is the effect of cyclic forces on the MSC differentiation. Recently, our group developed a thermoresponsive N-ethyl acrylamide/N-isopropylacrylamide (NIPAM/NEAM) hydrogel supplemented with gold nanorods that are able to convert near-infrared light into heat. Using light pulses allows for local hydrogel collapse and swelling with physiologically relevant force and frequency. In this study, MSCs are cultured on this hydrogel system with a patterned surface and exposed to intermittent or continuous actuation of the hydrogel for 3 days to study the effect of actuation on MSC differentiation. First, cells are harvested from the bone marrow of three donors and tested for their MSC phenotype, meeting the following criteria: the harvested cells are adherent and demonstrate a fibroblast-like bipolar morphology. They lack the expression of CD34 and CD45 but do express CD73, CD90, and CD105. Additionally, their differentiation potential into adipogenic, chondrogenic, and osteogenic lineages is validated by the addition of standardized differentiation media. Next, MSCs are exposed to intermittent or continuous actuation, which leads to a significantly enhanced cell spreading compared to nonactuated cells. Moreover, actuation results in nuclear translocation of Runt-related transcription factor 2 and the Yes-associated protein. Together, these results indicate that cyclic mechanical stimulation on a soft, ridged substrate modulates the MSC fate commitment in the direction of osteogenesis.
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Affiliation(s)
- Arturo Castro Nava
- DWI—Leibniz
Institute for Interactive Materials, Forckenbeckstrasse 50, Aachen D-52074, Germany
- Institute
for Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 1-2, Aachen D-52074, Germany
| | - Iris C. Doolaar
- DWI—Leibniz
Institute for Interactive Materials, Forckenbeckstrasse 50, Aachen D-52074, Germany
- Institute
for Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 1-2, Aachen D-52074, Germany
| | - Norina Labude-Weber
- Helmholtz
Institute for Biomedical Engineering, BioInterface Group, RWTH Aachen University, Pauwelsstrasse 20, Aachen D-52074, Germany
| | - Hanna Malyaran
- Helmholtz
Institute for Biomedical Engineering, BioInterface Group, RWTH Aachen University, Pauwelsstrasse 20, Aachen D-52074, Germany
- Interdisciplinary
Centre for Clinical Research, RWTH Aachen
University, Pauwelsstrasse
30, Aachen D-52074, Germany
| | - Susan Babu
- DWI—Leibniz
Institute for Interactive Materials, Forckenbeckstrasse 50, Aachen D-52074, Germany
- Institute
for Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 1-2, Aachen D-52074, Germany
| | - Yashoda Chandorkar
- DWI—Leibniz
Institute for Interactive Materials, Forckenbeckstrasse 50, Aachen D-52074, Germany
| | - Jacopo Di Russo
- DWI—Leibniz
Institute for Interactive Materials, Forckenbeckstrasse 50, Aachen D-52074, Germany
- Interdisciplinary
Centre for Clinical Research, RWTH Aachen
University, Pauwelsstrasse
30, Aachen D-52074, Germany
- Institute
of Molecular and Cellular Anatomy, RWTH
Aachen University, Pauwelsstrasse
30, Aachen D-52074, Germany
| | - Sabine Neuss
- Helmholtz
Institute for Biomedical Engineering, BioInterface Group, RWTH Aachen University, Pauwelsstrasse 20, Aachen D-52074, Germany
- Institute
of Pathology, RWTH Aachen University Hospital, Pauwelsstrasse 30, Aachen D-52074, Germany
| | - Laura De Laporte
- DWI—Leibniz
Institute for Interactive Materials, Forckenbeckstrasse 50, Aachen D-52074, Germany
- Institute
for Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 1-2, Aachen D-52074, Germany
- Institute
of Applied Medical Engineering, Department of Advanced Materials for
Biomedicine, RWTH Aachen University, Forckenbeckstraße 55, Aachen D-52074, Germany
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Faccioli LA, Dias ML, Martins-Santos R, Paredes BD, Takiya CM, dos Santos Goldenberg RC. Resident Liver Stem Cells. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:23-51. [DOI: 10.1016/b978-0-443-15289-4.00015-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Wang Y, She S, Li W, Zhu J, Li X, Yang F, Dai K. Inhibition of cGAS-STING pathway by stress granules after activation of M2 macrophages by human mesenchymal stem cells against drug induced liver injury. Mol Immunol 2024; 165:42-54. [PMID: 38150981 DOI: 10.1016/j.molimm.2023.12.005] [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: 07/08/2023] [Revised: 11/05/2023] [Accepted: 12/14/2023] [Indexed: 12/29/2023]
Abstract
OBJECTIVE Cells can produce stress granules (SGs) to protect itself from damage under stress. The cGAS-STING pathway is one of the important pattern recognition pathways in the natural immune system. This study was investigated whether human mesenchymal stem cells (hMSCs) could protect the liver by inducing M2 macrophages to produce SGs during acute drug induced liver injury (DILI) induced by acetaminophen (APAP). METHODS After intragastric administration of APAP in vivo to induce DILI mice model, hMSCs were injected into the tail vein. The co-culture system of hMSCs and M2 macrophages was established in vitro. It was further use SGs inhibitor anisomicin to intervene M2 macrophages. The liver histopathology, liver function, reactive oxygen species (ROS) level, apoptosis pathway, endoplasmic reticulum stress (ERS) level, SGs markers (G3BP1/TIA-1), cGAS-STING pathway, TNF-α, IL-6, IL-1β mRNA levels in liver tissue and M2 macrophages were observed. RESULTS In vivo experiments, it showed that hMSCs could alleviate liver injury, inhibite the level of ROS, apoptosis and ERS, protect liver function in DILI mice. The mount of M2 was increased in the liver. hMSCs could also induce the production of SGs, inhibit the cGAS-STING pathway and reduce TNF-α, IL-6, IL-1β mRNA expression. The results in vitro showed that hMSCs could induce the production of SGs in macrophages, inhibit the cGAS-STING pathway, promote the secretion of IL-4 and IL-13, and reduce TNF-α, IL-6, IL-1β mRNA level in cells. In the process of IL-4 inducing M2 macrophage activation, anisomycin could inhibit the production of SGs, activate the cGAS-STING pathway, and promote the inflammatory factor TNF-α, IL-6, IL-1β mRNA expression in cells. CONCLUSIONS HMSCs had a protective effect on acute DILI in mice induced by APAP. Its mechanism might involve in activating M2 type macrophages, promoting the production of SGs, inhibiting the cGAS-STING pathway, and reducing the expression of pro-inflammatory factors in macrophages, to reduce hepatocytes damage.
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Affiliation(s)
- Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Sha She
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Wenyuan Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jiling Zhu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Xun Li
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Fan Yang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Kai Dai
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, China.
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Mitaka T, Ichinohe N, Tanimizu N. "Small Hepatocytes" in the Liver. Cells 2023; 12:2718. [PMID: 38067145 PMCID: PMC10705974 DOI: 10.3390/cells12232718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 11/17/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023] Open
Abstract
Mature hepatocytes (MHs) in an adult rodent liver are categorized into the following three subpopulations based on their proliferative capability: type I cells (MH-I), which are committed progenitor cells that possess a high growth capability and basal hepatocytic functions; type II cells (MH-II), which possess a limited proliferative capability; and type III cells (MH-III), which lose the ability to divide (replicative senescence) and reach the final differentiated state. These subpopulations may explain the liver's development and growth after birth. Generally, small-sized hepatocytes emerge in mammal livers. The cells are characterized by being morphologically identical to hepatocytes except for their size, which is substantially smaller than that of ordinary MHs. We initially discovered small hepatocytes (SHs) in the primary culture of rat hepatocytes. We believe that SHs are derived from MH-I and play a role as hepatocytic progenitors to supply MHs. The population of MH-I (SHs) is distributed in the whole lobules, a part of which possesses a self-renewal capability, and decreases with age. Conversely, injured livers of experimental models and clinical cases showed the emergence of SHs. Studies demonstrate the involvement of SHs in liver regeneration. SHs that appeared in the injured livers are not a pure population but a mixture of two distinct origins, MH-derived and hepatic-stem-cell-derived cells. The predominant cell-derived SHs depend on the proliferative capability of the remaining MHs after the injury. This review will focus on the SHs that appeared in the liver and discuss the significance of SHs in liver regeneration.
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Affiliation(s)
- Toshihiro Mitaka
- Department of Tissue Development and Regeneration, Institute of Regenerative Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (N.I.); (N.T.)
| | - Norihisa Ichinohe
- Department of Tissue Development and Regeneration, Institute of Regenerative Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (N.I.); (N.T.)
| | - Naoki Tanimizu
- Department of Tissue Development and Regeneration, Institute of Regenerative Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (N.I.); (N.T.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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Hrncir HR, Hantelys F, Gracz AD. Panic at the Bile Duct: How Intrahepatic Cholangiocytes Respond to Stress and Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1440-1454. [PMID: 36870530 PMCID: PMC10548281 DOI: 10.1016/j.ajpath.2023.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/16/2023] [Accepted: 02/15/2023] [Indexed: 03/06/2023]
Abstract
In the liver, biliary epithelial cells (BECs) line intrahepatic bile ducts (IHBDs) and are primarily responsible for modifying and transporting hepatocyte-produced bile to the digestive tract. BECs comprise only 3% to 5% of the liver by cell number but are critical for maintaining choleresis through homeostasis and disease. To this end, BECs drive an extensive morphologic remodeling of the IHBD network termed ductular reaction (DR) in response to direct injury or injury to the hepatic parenchyma. BECs are also the target of a broad and heterogenous class of diseases termed cholangiopathies, which can present with phenotypes ranging from defective IHBD development in pediatric patients to progressive periductal fibrosis and cancer. DR is observed in many cholangiopathies, highlighting overlapping similarities between cell- and tissue-level responses by BECs across a spectrum of injury and disease. The following core set of cell biological BEC responses to stress and injury may moderate, initiate, or exacerbate liver pathophysiology in a context-dependent manner: cell death, proliferation, transdifferentiation, senescence, and acquisition of neuroendocrine phenotype. By reviewing how IHBDs respond to stress, this review seeks to highlight fundamental processes with potentially adaptive or maladaptive consequences. A deeper understanding of how these common responses contribute to DR and cholangiopathies may identify novel therapeutic targets in liver disease.
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Affiliation(s)
- Hannah R Hrncir
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia
| | - Fransky Hantelys
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia
| | - Adam D Gracz
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, Georgia.
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Yang H, Chen J, Li J. Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure. Front Immunol 2023; 14:1243220. [PMID: 37744328 PMCID: PMC10513107 DOI: 10.3389/fimmu.2023.1243220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Acute liver failure (ALF) is a high-mortality syndrome for which liver transplantation is considered the only effective treatment option. A shortage of donor organs, high costs and surgical complications associated with immune rejection constrain the therapeutic effects of liver transplantation. Recently, mesenchymal stem cell (MSC) therapy was recognized as an alternative strategy for liver transplantation. Bone marrow mesenchymal stem cells (BMSCs) have been used in clinical trials of several liver diseases due to their ease of acquisition, strong proliferation ability, multipotent differentiation, homing to the lesion site, low immunogenicity and anti-inflammatory and antifibrotic effects. In this review, we comprehensively summarized the harvest and culture expansion strategies for BMSCs, the development of animal models of ALF of different aetiologies, the critical mechanisms of BMSC therapy for ALF and the challenge of clinical application.
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Affiliation(s)
| | | | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Zhang W, Wang T, Xue Y, Zhan B, Lai Z, Huang W, Peng X, Zhou Y. Research progress of extracellular vesicles and exosomes derived from mesenchymal stem cells in the treatment of oxidative stress-related diseases. Front Immunol 2023; 14:1238789. [PMID: 37646039 PMCID: PMC10461809 DOI: 10.3389/fimmu.2023.1238789] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/24/2023] [Indexed: 09/01/2023] Open
Abstract
There is growing evidence that mesenchymal stem cell-derived extracellular vesicles and exosomes can significantly improve the curative effect of oxidative stress-related diseases. Mesenchymal stem cell extracellular vesicles and exosomes (MSC-EVs and MSC-Exos) are rich in bioactive molecules and have many biological regulatory functions. In this review, we describe how MSC-EVs and MSC-Exos reduce the related markers of oxidative stress and inflammation in various systemic diseases, and the molecular mechanism of MSC-EVs and MSC-Exos in treating apoptosis and vascular injury induced by oxidative stress. The results of a large number of experimental studies have shown that both local and systemic administration can effectively inhibit the oxidative stress response in diseases and promote the survival and regeneration of damaged parenchymal cells. The mRNA and miRNAs in MSC-EVs and MSC-Exos are the most important bioactive molecules in disease treatment, which can inhibit the apoptosis, necrosis and oxidative stress of lung, heart, kidney, liver, bone, skin and other cells, and promote their survive and regenerate.
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Affiliation(s)
- Wenwen Zhang
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Tingyu Wang
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Yuanye Xue
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Bingbing Zhan
- School of Pharmaceutical Sciences, Guangdong Medical University, Dongguan, China
| | - Zengjie Lai
- The Second Clinical Medical College of Guangdong Medical University, Dongguan, China
| | - Wenjie Huang
- School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Xinsheng Peng
- Biomedical Innovation Center, Guangdong Medical University, Dongguan, China
- Institute of Marine Medicine, Guangdong Medical University, Zhanjiang, China
| | - Yanfang Zhou
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
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Ichinohe N, Tanimizu N, Ishigami K, Yoshioka Y, Fujitani N, Ochiya T, Takahashi M, Mitaka T. CINC-2 and miR-199a-5p in EVs secreted by transplanted Thy1 + cells activate hepatocytic progenitor cell growth in rat liver regeneration. Stem Cell Res Ther 2023; 14:134. [PMID: 37194082 DOI: 10.1186/s13287-023-03346-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 04/12/2023] [Indexed: 05/18/2023] Open
Abstract
BACKGROUND Small hepatocyte-like progenitor cells (SHPCs) are hepatocytic progenitor cells that transiently form clusters in rat livers treated with retrorsine (Ret) that underwent 70% partial hepatectomy (PH). We previously reported that transplantation of Thy1+ cells obtained from D-galactosamine-treated livers promotes SHPC expansion, thereby accelerating liver regeneration. Extracellular vesicles (EVs) secreted by Thy1+ cells induce sinusoidal endothelial cells (SECs) and Kupffer cells (KCs) to secrete IL17B and IL25, respectively, thereby activating SHPCs through IL17 receptor B (RB) signaling. This study aimed to identify the inducers of IL17RB signaling and growth factors for SHPC proliferation in EVs secreted by Thy1+ cells (Thy1-EVs). METHODS Thy1+ cells isolated from the livers of rats treated with D-galactosamine were cultured. Although some liver stem/progenitor cells (LSPCs) proliferated to form colonies, others remained as mesenchymal cells (MCs). Thy1-MCs or Thy1-LSPCs were transplanted into Ret/PH-treated livers to examine their effects on SHPCs. EVs were isolated from the conditioned medium (CM) of Thy1-MCs and Thy1-LSPCs. Small hepatocytes (SHs) isolated from adult rat livers were used to identify factors regulating cell growth in Thy1-EVs. RESULTS The size of SHPC clusters transplanted with Thy1-MCs was significantly larger than that of SHPC clusters transplanted with Thy1-LSPCs (p = 0.02). A comprehensive analysis of Thy1-MC-EVs revealed that miR-199a-5p, cytokine-induced neutrophil chemoattractant-2 (CINC-2), and monocyte chemotactic protein 1 (MCP-1) were candidates for promoting SHPC growth. Additionally, miR-199a-5p mimics promoted the growth of SHs (p = 0.02), whereas CINC-2 and MCP-1 did not. SECs treated with CINC-2 induced Il17b expression. KCs treated with Thy1-EVs induced the expression of CINC-2, Il25, and miR-199a-5p. CM derived from SECs treated with CINC-2 accelerated the growth of SHs (p = 0.03). Similarly, CM derived from KCs treated with Thy1-EVs and miR-199a-5p mimics accelerated the growth of SHs (p = 0.007). In addition, although miR-199a-overexpressing EVs could not enhance SHPC proliferation, transplantation of miR-199a-overexpressing Thy1-MCs could promote the expansion of SHPC clusters. CONCLUSION Thy1-MC transplantation may accelerate liver regeneration owing to SHPC expansion, which is induced by CINC-2/IL17RB signaling and miR-199a-5p via SEC and KC activation.
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Affiliation(s)
- Norihisa Ichinohe
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-Ku, Sapporo, 060-8556, Japan.
| | - Naoki Tanimizu
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-Ku, Sapporo, 060-8556, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Keisuke Ishigami
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-Ku, Sapporo, 060-8556, Japan
| | - Yusuke Yoshioka
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Naoki Fujitani
- Department of Biochemistry, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Motoko Takahashi
- Department of Biochemistry, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Toshihiro Mitaka
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-Ku, Sapporo, 060-8556, Japan.
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10
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Shafritz DA, Ebrahimkhani MR, Oertel M. Therapeutic Cell Repopulation of the Liver: From Fetal Rat Cells to Synthetic Human Tissues. Cells 2023; 12:529. [PMID: 36831196 PMCID: PMC9954009 DOI: 10.3390/cells12040529] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 02/10/2023] Open
Abstract
Progenitor cells isolated from the fetal liver can provide a unique cell source to generate new healthy tissue mass. Almost 20 years ago, it was demonstrated that rat fetal liver cells repopulate the normal host liver environment via a mechanism akin to cell competition. Activin A, which is produced by hepatocytes, was identified as an important player during cell competition. Because of reduced activin receptor expression, highly proliferative fetal liver stem/progenitor cells are resistant to activin A and therefore exhibit a growth advantage compared to hepatocytes. As a result, transplanted fetal liver cells are capable of repopulating normal livers. Important for cell-based therapies, hepatic stem/progenitor cells containing repopulation potential can be separated from fetal hematopoietic cells using the cell surface marker δ-like 1 (Dlk-1). In livers with advanced fibrosis, fetal epithelial stem/progenitor cells differentiate into functional hepatic cells and out-compete injured endogenous hepatocytes, which cause anti-fibrotic effects. Although fetal liver cells efficiently repopulate the liver, they will likely not be used for human cell transplantation. Thus, utilizing the underlying mechanism of repopulation and developed methods to produce similar growth-advantaged cells in vitro, e.g., human induced pluripotent stem cells (iPSCs), this approach has great potential for developing novel cell-based therapies in patients with liver disease. The present review gives a brief overview of the classic cell transplantation models and various cell sources studied as donor cell candidates. The advantages of fetal liver-derived stem/progenitor cells are discussed, as well as the mechanism of liver repopulation. Moreover, this article reviews the potential of in vitro developed synthetic human fetal livers from iPSCs and their therapeutic benefits.
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Affiliation(s)
- David A. Shafritz
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Mo R. Ebrahimkhani
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15213, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Michael Oertel
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15213, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
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11
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Bittmann S, Villalon G, Moschuring-Alieva E, Luchter E, Bittmann L. Current and Novel Therapeutical Approaches of Classical Homocystinuria in Childhood With Special Focus on Enzyme Replacement Therapy, Liver-Directed Therapy and Gene Therapy. J Clin Med Res 2023; 15:76-83. [PMID: 36895619 PMCID: PMC9990725 DOI: 10.14740/jocmr4843] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 01/09/2023] [Indexed: 03/05/2023] Open
Abstract
Classical homocystinuria is a hereditary defect of the enzyme cystathionine beta synthase, which is produced in the liver. If this enzyme fails, the synthesis pathway of cysteine from methionine is interrupted, leading to the accumulation of homocysteine in the blood plasma and homocysteine in the urine. After birth, the children are unremarkable except for the characteristic laboratory findings. Symptoms rarely appear before the second year of life. The most common symptom is a prolapse of the crystalline lens. This finding is seen in 70% of untreated 10-year-old affected individuals. As the earliest symptom, psychomotor retardation occurs in the majority of patients already during the first two years of life. Limiting factors in terms of life expectancy are thromboembolism, peripheral arterial disease, myocardial infarction, and stroke. These symptoms are due to the damage to the vessels caused by the elevated amino acid levels. About 30% suffer a thromboembolic event by the age of 20, about half by the age of 30. This review focus on present and new therapeutical approaches like the role of enzyme replacement with presentation of different novel targets in research like pegtibatinase, pegtarviliase, CDX-6512, erymethionase, chaperones, proteasome inhibitors and probiotic treatment with SYNB 1353. Furthermore, we analyze the role of liver-directed therapy with three dimensional (3D) bioprinting, liver bioengineering of liver organoids in vitro and liver transplantation. The role of different gene therapy options to treat and cure this extremely rare disease in childhood will be discussed.
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Affiliation(s)
- Stefan Bittmann
- Ped Mind Institute, Department of Pediatrics, Medical and Finance Center Epe, D-48599 Gronau, Germany
| | - Gloria Villalon
- Ped Mind Institute, Department of Pediatrics, Medical and Finance Center Epe, D-48599 Gronau, Germany
| | - Elena Moschuring-Alieva
- Ped Mind Institute, Department of Pediatrics, Medical and Finance Center Epe, D-48599 Gronau, Germany
| | - Elisabeth Luchter
- Ped Mind Institute, Department of Pediatrics, Medical and Finance Center Epe, D-48599 Gronau, Germany
| | - Lara Bittmann
- Ped Mind Institute, Department of Pediatrics, Medical and Finance Center Epe, D-48599 Gronau, Germany
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12
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The Long Telling Story of "Endothelial Progenitor Cells": Where Are We at Now? Cells 2022; 12:cells12010112. [PMID: 36611906 PMCID: PMC9819021 DOI: 10.3390/cells12010112] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
Endothelial progenitor cells (EPCs): The name embodies years of research and clinical expectations, but where are we now? Do these cells really represent the El Dorado of regenerative medicine? Here, past and recent literature about this eclectic, still unknown and therefore fascinating cell population will be discussed. This review will take the reader through a temporal journey that, from the first discovery, will pass through years of research devoted to attempts at their definition and understanding their biology in health and disease, ending with the most recent evidence about their pathobiological role in cardiovascular disease and their recent applications in regenerative medicine.
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13
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Quesenberry PJ, Wen S, Goldberg LR, Dooner MS. The universal stem cell. Leukemia 2022; 36:2784-2792. [PMID: 36307485 PMCID: PMC9712109 DOI: 10.1038/s41375-022-01715-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/26/2022] [Accepted: 09/22/2022] [Indexed: 11/08/2022]
Abstract
Current dogma is that there exists a hematopoietic pluripotent stem cell, resident in the marrow, which is quiescent, but with tremendous proliferative and differentiative potential. Furthermore, the hematopoietic system is essentially hierarchical with progressive differentiation from the pluripotent stem cells to different classes of hematopoietic cells. However, results summarized here indicate that the marrow pluripotent hematopoietic stem cell is actively cycling and thus continually changing phenotype. As it progresses through cell cycle differentiation potential changes as illustrated by sequential changes in surface expression of B220 and GR-1 epitopes. Further data indicated that the potential of purified hematopoietic stem cells extends to multiple other non-hematopoietic cells. It appears that marrow stem cells will give rise to epithelial pulmonary cells at certain points in cell cycle. Thus, it appears that the marrow "hematopoietic" stem cell is also a stem cell for other non-hematopoietic tissues. These observations give rise to the concept of a universal stem cell. The marrow stem cell is not limited to hematopoiesis and its differentiation potential continually changes as it transits cell cycle. Thus, there is a universal stem cell in the marrow which alters its differentiation potential as it progresses through cell cycle. This potential is expressed when it resides in tissues compatible with its differentiation potential, at a particular point in cell cycle transit, or when it interacts with vesicles from that tissue.
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Affiliation(s)
- Peter J Quesenberry
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA.
| | - Sicheng Wen
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA
| | - Laura R Goldberg
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA
- Division of Hematology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Mark S Dooner
- Division of Hematology/Oncology, Brown University, Rhode Island Hospital, Providence, RI, 02903, USA
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14
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Damaskos C, Garmpis N, Dimitroulis D, Garmpi A, Psilopatis I, Sarantis P, Koustas E, Kanavidis P, Prevezanos D, Kouraklis G, Karamouzis MV, Marinos G, Kontzoglou K, Antoniou EA. Targeted Therapies for Hepatocellular Carcinoma Treatment: A New Era Ahead-A Systematic Review. Int J Mol Sci 2022; 23:ijms232214117. [PMID: 36430594 PMCID: PMC9698799 DOI: 10.3390/ijms232214117] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.
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Affiliation(s)
- Christos Damaskos
- Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Correspondence: ; Tel.: +30-694-846-7790
| | - Nikolaos Garmpis
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Dimitroulis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Iason Psilopatis
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Prodromos Kanavidis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | | | - Gregory Kouraklis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michail V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Marinos
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Konstantinos Kontzoglou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Efstathios A. Antoniou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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15
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Liver Regeneration by Hematopoietic Stem Cells: Have We Reached the End of the Road? Cells 2022; 11:cells11152312. [PMID: 35954155 PMCID: PMC9367594 DOI: 10.3390/cells11152312] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/22/2022] [Accepted: 07/22/2022] [Indexed: 02/01/2023] Open
Abstract
The liver is the organ with the highest regenerative capacity in the human body. However, various insults, including viral infections, alcohol or drug abuse, and metabolic overload, may cause chronic inflammation and fibrosis, leading to irreversible liver dysfunction. Despite advances in surgery and pharmacological treatments, liver diseases remain a leading cause of death worldwide. To address the shortage of donor liver organs for orthotopic liver transplantation, cell therapy in liver disease has emerged as a promising regenerative treatment. Sources include primary hepatocytes or functional hepatocytes generated from the reprogramming of induced pluripotent stem cells (iPSC). Different types of stem cells have also been employed for transplantation to trigger regeneration, including hematopoietic stem cells (HSCs), mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs) as well as adult and fetal liver progenitor cells. HSCs, usually defined by the expression of CD34 and CD133, and MSCs, defined by the expression of CD105, CD73, and CD90, are attractive sources due to their autologous nature, ease of isolation and cryopreservation. The present review focuses on the use of bone marrow HSCs for liver regeneration, presenting evidence for an ongoing crosstalk between the hematopoietic and the hepatic system. This relationship commences during embryogenesis when the fetal liver emerges as the crossroads between the two systems converging the presence of different origins of cells (mesoderm and endoderm) in the same organ. Ample evidence indicates that the fetal liver supports the maturation and expansion of HSCs during development but also later on in life. Moreover, the fact that the adult liver remains one of the few sites for extramedullary hematopoiesis—albeit pathological—suggests that this relationship between the two systems is ongoing. Can, however, the hematopoietic system offer similar support to the liver? The majority of clinical studies using hematopoietic cell transplantation in patients with liver disease report favourable observations. The underlying mechanism—whether paracrine, fusion or transdifferentiation or a combination of the three—remains to be confirmed.
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16
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Chen P, Zhou YK, Han CS, Chen LJ, Wang YM, Zhuang ZM, Lin S, Zhou YH, Jiang JH, Yang RL. Stem Cells From Human Exfoliated Deciduous Teeth Alleviate Liver Cirrhosis via Inhibition of Gasdermin D-Executed Hepatocyte Pyroptosis. Front Immunol 2022; 13:860225. [PMID: 35634294 PMCID: PMC9133376 DOI: 10.3389/fimmu.2022.860225] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 03/29/2022] [Indexed: 11/29/2022] Open
Abstract
Liver cirrhosis represents a type of end-stage liver disease with few effective therapies, which was characterized by damaged functional liver tissue due to long-term inflammation. Gasdermin D (GSDMD)-executed programmed necrosis is reported to be involved in inflammation. However, the role of GSDMD in liver cirrhosis remains unclear. In this study, we used a CCl4-induced cirrhosis model and found stem cells from human exfoliated deciduous teeth (SHED) infusion showed profound therapeutic effects for liver cirrhosis. Mechanistically, NLRP3 inflammasome-activated GSDMD and its pyroptosis were upregulated in liver cirrhosis, while SHED infusion could suppress the expression of GSDMD and Caspase-1, resulting in reduced hepatocyte pyroptosis and inflammatory cytokine IL-1β release. Consistently, SHED could inhibit the elevated expression of NLRP3, GSDMD and Caspase-1 induced by CCl4 treatment in vitro co-culture system, which was mediated by decreasing reactive oxygen species (ROS) generation. Moreover, the pyroptosis inhibitor disulfiram showed similar therapeutic effects for liver cirrhosis as SHED. In conclusion, SHED alleviates CCl4-induced liver cirrhosis via inhibition of hepatocytes pyroptosis. Our findings could provide a potential treatment strategy and novel target for liver cirrhosis.
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Affiliation(s)
- Peng Chen
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.,National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.,Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Yi-Kun Zhou
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.,National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.,Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Chun-Shan Han
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.,National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.,Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Liu-Jing Chen
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.,National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.,Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Yi-Ming Wang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.,National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.,Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Zi-Meng Zhuang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.,National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.,Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Shuai Lin
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.,National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.,Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Yan-Heng Zhou
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.,National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.,Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Jiu-Hui Jiang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.,National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.,Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Rui-Li Yang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China.,National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China.,Beijing Key Laboratory of Digital Stomatology, Beijing, China
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17
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Wang J, Wang T, Zhang F, Zhang Y, Guo Y, Jiang X, Yang B. Roles of circular RNAs in osteogenic differentiation of bone marrow mesenchymal stem cells (Review). Mol Med Rep 2022; 26:227. [PMID: 35593273 PMCID: PMC9178710 DOI: 10.3892/mmr.2022.12743] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/10/2022] [Indexed: 11/06/2022] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs) can differentiate into osteoblasts, chondrocytes, adipocytes and even myoblasts, and are therefore defined as pluripotent cells. BMSCs have become extremely important seed cells in gene therapy, tissue engineering, cell replacement therapy and regenerative medicine due to their potential in multilineage differentiation, self‑renewal, immune regulation and other fields. Circular RNAs (circRNAs) are a class of non‑coding RNAs that are widely present in eukaryotic cells. Unlike standard linear RNAs, circRNAs form covalently closed continuous loops with no 5' or 3' polarity. circRNAs are abundantly expressed in cells and tissues, and are highly conserved and relatively stable during evolution. Numerous studies have shown that circRNAs play an important role in the osteogenic differentiation of BMSCs. Further studies on the role of circRNAs in the osteogenic differentiation of BMSCs can provide a new theoretical and experimental basis for bone tissue engineering and clinical treatment.
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Affiliation(s)
- Jicheng Wang
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Tengyun Wang
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Fujie Zhang
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Yangyang Zhang
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Yongzhi Guo
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Xin Jiang
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Bo Yang
- Department of Joint Surgery, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
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18
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Lan T, Qian S, Tang C, Gao J. Role of Immune Cells in Biliary Repair. Front Immunol 2022; 13:866040. [PMID: 35432349 PMCID: PMC9005827 DOI: 10.3389/fimmu.2022.866040] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/08/2022] [Indexed: 02/06/2023] Open
Abstract
The biliary system is comprised of cholangiocytes and plays an important role in maintaining liver function. Under normal conditions, cholangiocytes remain in the stationary phase and maintain a very low turnover rate. However, the robust biliary repair is initiated in disease conditions, and different repair mechanisms can be activated depending on the pathological changes. During biliary disease, immune cells including monocytes, lymphocytes, neutrophils, and mast cells are recruited to the liver. The cellular interactions between cholangiocytes and these recruited immune cells as well as hepatic resident immune cells, including Kupffer cells, determine disease outcomes. However, the role of immune cells in the initiation, regulation, and suspension of biliary repair remains elusive. The cellular processes of cholangiocyte proliferation, progenitor cell differentiation, and hepatocyte-cholangiocyte transdifferentiation during biliary diseases are reviewed to manifest the underlying mechanism of biliary repair. Furthermore, the potential role of immune cells in crucial biliary repair mechanisms is highlighted. The mechanisms of biliary repair in immune-mediated cholangiopathies, inherited cholangiopathies, obstructive cholangiopathies, and cholangiocarcinoma are also summarized. Additionally, novel techniques that could clarify the underlying mechanisms of biliary repair are displayed. Collectively, this review aims to deepen the understanding of the mechanisms of biliary repair and contributes potential novel therapeutic methods for treating biliary diseases.
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Affiliation(s)
- Tian Lan
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Shuaijie Qian
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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19
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Li J, Wang Q, An Y, Chen X, Xing Y, Deng Q, Li Z, Wang S, Dai X, Liang N, Hou Y, Yang H, Shang Z. Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Mesenchymal Stem/Stromal Cells Derived from Human Placenta. Front Cell Dev Biol 2022; 10:836887. [PMID: 35450295 PMCID: PMC9017713 DOI: 10.3389/fcell.2022.836887] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/09/2022] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stem/stromal cells derived from placenta (PMSCs) are an attractive source for regenerative medicine because of their multidifferentiation potential and immunomodulatory capabilities. However, the cellular and molecular heterogeneity of PMSCs has not been fully characterized. Here, we applied single-cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin sequencing (scATAC-seq) techniques to cultured PMSCs from human full-term placenta. Based on the inferred characteristics of cell clusters, we identify several distinct subsets of PMSCs with specific characteristics, including immunomodulatory-potential and highly proliferative cell states. Furthermore, integrative analysis of gene expression and chromatin accessibility showed a clearer chromatin accessibility signature than those at the transcriptional level on immunomodulatory-related genes. Cell cycle gene-related heterogeneity can be more easily distinguished at the transcriptional than the chromatin accessibility level in PMSCs. We further reveal putative subset-specific cis-regulatory elements regulating the expression of immunomodulatory- and proliferation-related genes in the immunomodulatory-potential and proliferative subpopulations, respectively. Moreover, we infer a novel transcription factor PRDM1, which might play a crucial role in maintaining immunomodulatory capability by activating PRDM1-regulon loop. Collectively, our study first provides a comprehensive and integrative view of the transcriptomic and epigenomic features of PMSCs, which paves the way for a deeper understanding of cellular heterogeneity and offers fundamental biological insight of PMSC subset-based cell therapy.
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Affiliation(s)
- Jinlu Li
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Quanlei Wang
- BGI-Shenzhen, Shenzhen, China
- Key Laboratory of Regenerative Medicine of Ministry of Education, Biology Postdoctoral Research Station, Jinan University, Guangzhou, China
| | | | | | - Yanan Xing
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Qiuting Deng
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Zelong Li
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Shengpeng Wang
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | - Xi Dai
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
| | | | | | - Huanming Yang
- BGI-Shenzhen, Shenzhen, China
- James D. Watson Institute of Genome Sciences, Hangzhou, China
| | - Zhouchun Shang
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
- BGI-Shenzhen, Shenzhen, China
- BGI College, Northwest University, Xi’an, China
- *Correspondence: Zhouchun Shang,
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20
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Phenotypic and functional properties of dedifferentiated fat cells derived from infrapatellar fat pad. Regen Ther 2022; 19:35-46. [PMID: 35059478 PMCID: PMC8739472 DOI: 10.1016/j.reth.2021.12.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 12/12/2021] [Accepted: 12/20/2021] [Indexed: 01/03/2023] Open
Abstract
Introduction Mature adipocyte-derived dedifferentiated fat cells (DFATs) are mesenchymal stem cell (MSC)-like cells with high proliferative ability and multilineage differentiation potential. In this study, we first examined whether DFATs can be prepared from infrapatellar fat pad (IFP) and then compared phenotypic and functional properties of IFP-derived DFATs (IFP-DFATs) with those of subcutaneous adipose tissue (SC)-derived DFATs (SC-DFATs). Methods Mature adipocytes isolated from IFP and SC in osteoarthritis patients (n = 7) were cultured by ceiling culture method to generate DFATs. Obtained IFP-DFATs and SC-DFATs were subjected to flow cytometric and microarray analysis to compare their immunophenotypes and gene expression profiles. Cell proliferation assay and adipogenic, osteogenic, and chondrogenic differentiation assays were performed to evaluate their functional properties. Results DFATs could be prepared from IFP and SC with similar efficiency. IFP-DFATs and SC-DFATs exhibited similar immunophenotypes (CD73+, CD90+, CD105+, CD31-, CD45-, HLA-DR-) and tri-lineage (adipogenic, osteogenic, and chondrogenic) differentiation potential, consistent with the minimal criteria for defining MSCs. Microarray analysis revealed that the gene expression profiles in IFP-DFATs were very similar to those in SC-DFATs, although there were certain number of genes that showed different levels of expression. The proliferative activity in IFP-DFATs was significantly (p < 0.05) higher than that in the SC-DFATs. IFP-DFATs showed higher chondrogenic differentiation potential than SC-DFATs in regard to production of soluble galactosaminogalactan and gene expression of type II collagen. Conclusions IFP-DFATs showed higher cellular proliferative potential and higher chondrogenic differentiation capacity than SC-DFATs. IFP-DFAT cells may be an attractive cell source for chondrogenic regeneration.
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21
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Guo Z, Pu S, Li Y, Wang X, Hu S, Zhao H, Yang C, Zhou Z. Functional characterization of CD49f + hepatic stem/progenitor cells in adult mice liver. J Mol Histol 2022; 53:239-256. [PMID: 35166962 DOI: 10.1007/s10735-022-10063-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 01/27/2022] [Indexed: 10/19/2022]
Abstract
Hepatic Stem/progenitor cells (HSPCs) have gained a large amount of interest for treating acute liver disease. However, the isolation and identification of HSPCs are unclear due to the lack of cell-specific surface markers. To isolate adult HSPCs, we used cell surface-marking antibodies, including CD49f and Sca-1. Two subsets of putative HSPCs, Lin-CD45-Sca-1-CD49f+ (CD49f+) and Lin-CD45-Sca-1+CD49f- (Sca-1+) cells, were isolated from adult mice liver by flow cytometry. Robust proliferative activity and clonogenic activity were found in both CD49f+ and Sca-1+ cells through colony-forming tests and cell cycle analyses. Immunofluorescence staining revealed that CD49f+ cells expressed ALB and CK-19 while Sca-1+ cells expressed only ALB, indicating that CD49f+ cells were bipotential and capable of differentiating into hepatocyte and cholangiocyte. Consequently, PAS stain showed that differentiated CD49f+ and Sca-1+ cells synthesised glycogen, indicating they could differentiate into functional hepatocytes. mRNA expression profile indicated that both CD49f+ and Sca-1+ cells showed differential expression of genes that are associated with liver progenitor function such as Sox9 and EpCam. Moreover, two subsets of putative HSPCs were activated by DDC and we found that their abundance and proliferation increased with age. In summary, we hypothesized that CD49f+ cells were a type of potential HSPCs and may be utilised for clinical stem cell therapy.
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Affiliation(s)
- Ziqi Guo
- School of Life Sciences, Guangxi Normal University, Guilin, 541004, China.,Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, 541004, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Shiming Pu
- School of Life Sciences, Guangxi Normal University, Guilin, 541004, China.,Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, 541004, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Yun Li
- School of Life Sciences, Guangxi Normal University, Guilin, 541004, China.,Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, 541004, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Xiaoxia Wang
- School of Life Sciences, Guangxi Normal University, Guilin, 541004, China.,Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, 541004, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Suying Hu
- School of Life Sciences, Guangxi Normal University, Guilin, 541004, China.,Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, 541004, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Hongxia Zhao
- School of Life Sciences, Guangxi Normal University, Guilin, 541004, China.,Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, 541004, China.,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, 541004, China
| | - Cheng Yang
- School of Life Sciences, Guangxi Normal University, Guilin, 541004, China. .,Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, 541004, China. .,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, 541004, China.
| | - Zuping Zhou
- School of Life Sciences, Guangxi Normal University, Guilin, 541004, China. .,Guangxi Universities Key Laboratory of Stem Cell and Biopharmaceutical Technology, Guangxi Normal University, Guilin, 541004, China. .,Research Center for Biomedical Sciences, Guangxi Normal University, Guilin, 541004, China.
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Adult Stem Cell Therapy as Regenerative Medicine for End-Stage Liver Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1401:57-72. [DOI: 10.1007/5584_2022_719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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23
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Shi X, Jiang N, Mao J, Luo D, Liu Y. Mesenchymal stem cell‐derived exosomes for organ development and cell‐free therapy. NANO SELECT 2021. [DOI: 10.1002/nano.202000286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Xin Shi
- Center and School of Stomatology Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan P.R. China
- Laboratory of Biomimetic Nanomaterials Department of Orthodontics National Engineering Laboratory for Digital and Material Technology of Stomatology Beijing Key Laboratory of Digital Stomatology Peking University School and Hospital of Stomatology Beijing P.R. China
| | - Nan Jiang
- Laboratory of Biomimetic Nanomaterials Department of Orthodontics National Engineering Laboratory for Digital and Material Technology of Stomatology Beijing Key Laboratory of Digital Stomatology Peking University School and Hospital of Stomatology Beijing P.R. China
- Central Laboratory National Engineering Laboratory for Digital and Material Technology of Stomatology Beijing Key Laboratory of Digital Stomatology Peking University School and Hospital of Stomatology Beijing P.R. China
| | - Jing Mao
- Center and School of Stomatology Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan P.R. China
| | - Dan Luo
- CAS Center for Excellence in Nanoscience Beijing Key Laboratory of Micro‐nano Energy and Sensor Beijing Institute of Nanoenergy and Nanosystems Chinese Academy of Sciences Beijing P.R. China
| | - Yan Liu
- Laboratory of Biomimetic Nanomaterials Department of Orthodontics National Engineering Laboratory for Digital and Material Technology of Stomatology Beijing Key Laboratory of Digital Stomatology Peking University School and Hospital of Stomatology Beijing P.R. China
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24
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Stem Cells an Overview. Stem Cells 2021. [DOI: 10.1007/978-981-16-1638-9_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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25
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Zhou Q, Fan L, Li J. Liver Regeneration and Tissue Engineering. ARTIFICIAL LIVER 2021:73-94. [DOI: 10.1007/978-981-15-5984-6_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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26
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Hou Y, Lin W, Li Y, Sun Y, Liu Y, Chen C, Jiang X, Li G, Xu L. De-osteogenic-differentiated mesenchymal stem cells accelerate fracture healing by mir-92b. J Orthop Translat 2020; 27:25-32. [PMID: 33344169 PMCID: PMC7736910 DOI: 10.1016/j.jot.2020.10.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 10/05/2020] [Accepted: 10/23/2020] [Indexed: 12/20/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) are promising targets for therapeutic use in regenerative medicine and tissue engineering. In the previous study, we have found that MSCs could be reverted to a primitive stem cell population after in vitro induction of osteogenic and de-osteogenic differentiation (de-osteogenic differentiated MSCs, De-Os-MSCs). De-Os-MSCs showed improved cell survival and osteogenic potential. However, the underlying mechanism and its potential effect on fracture healing has not been explored. Methods MSCs were isolated from the rat bone marrow. MicroRNAs were cloned into lentiviral vectors and transduced into MSCs to observe the effects on osteogenesis. The expression levels of marker genes were evaluated by quantitative RT-PCR. Ectopic bone formation model was used to evaluate the bone regeneration ability of mir-92b transduced MSCs in vivo. An open femur fracture model was established, and MSCs or De-Os-MSCs were administrated to the fracture sites. Histological, biomechanical and microCT analysis were used to evaluate the quality of bone. Results In the present study, we found that mir-92b was significantly increased in the secretions of De-Os-MSCs. And mir-92b could promote the osteogenic differentiation potential of MSCs by activating pERK and JNK signaling pathways. The ectopic bone formation assay showed that MSCs overexpressing mir-92b formed more bone like tissues in vivo. Most importantly, we found local administration of De-Os-MSCs could accelerate fracture healing using an open femur fracture model in rats. The quality of bone property was much better as shown by microCT and biomechanical testing. Conclusion Taken together, our study demonstrated that mir-92b promoted osteogenesis of MSCs, which was partially accounted for the enhanced osteogenic differentiation potential of De-Os-MSCs. And De-Os-MSCs had shown better regenerative capacity in accelerating fracture healing when they were locally given. The translational potential of this article De-Os-MSCs could be used to accelerate fracture healing, and reduce the occurrence of delayed unions and non-unions.
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Affiliation(s)
- Yonghui Hou
- Key Laboratory of Orthopaedics & Traumatology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Lingnan Medical Research Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Weiping Lin
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China
| | - Ying Li
- Lingnan Medical Research Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuxin Sun
- Department of Orthopaedics and Traumatology, Bao-An District People's Hospital, Shenzhen, PR China
| | - Yamei Liu
- Departments of Diagnostics of Traditional Chinese Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
| | - Chen Chen
- Departments of Diagnostics of Traditional Chinese Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
| | - Xiaohua Jiang
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Gang Li
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China.,Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China
| | - Liangliang Xu
- Lingnan Medical Research Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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27
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Cun X, Hosta-Rigau L. Topography: A Biophysical Approach to Direct the Fate of Mesenchymal Stem Cells in Tissue Engineering Applications. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E2070. [PMID: 33092104 PMCID: PMC7590059 DOI: 10.3390/nano10102070] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/16/2020] [Accepted: 10/16/2020] [Indexed: 12/17/2022]
Abstract
Tissue engineering is a promising strategy to treat tissue and organ loss or damage caused by injury or disease. During the past two decades, mesenchymal stem cells (MSCs) have attracted a tremendous amount of interest in tissue engineering due to their multipotency and self-renewal ability. MSCs are also the most multipotent stem cells in the human adult body. However, the application of MSCs in tissue engineering is relatively limited because it is difficult to guide their differentiation toward a specific cell lineage by using traditional biochemical factors. Besides biochemical factors, the differentiation of MSCs also influenced by biophysical cues. To this end, much effort has been devoted to directing the cell lineage decisions of MSCs through adjusting the biophysical properties of biomaterials. The surface topography of the biomaterial-based scaffold can modulate the proliferation and differentiation of MSCs. Presently, the development of micro- and nano-fabrication techniques has made it possible to control the surface topography of the scaffold precisely. In this review, we highlight and discuss how the main topographical features (i.e., roughness, patterns, and porosity) are an efficient approach to control the fate of MSCs and the application of topography in tissue engineering.
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Affiliation(s)
| | - Leticia Hosta-Rigau
- DTU Health Tech, Centre for Nanomedicine and Theranostics, Technical University of Denmark, Nils Koppels Allé, Building 423, 2800 Kgs. Lyngby, Denmark;
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28
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Qiu C, Ge Z, Cui W, Yu L, Li J. Human Amniotic Epithelial Stem Cells: A Promising Seed Cell for Clinical Applications. Int J Mol Sci 2020; 21:ijms21207730. [PMID: 33086620 PMCID: PMC7594030 DOI: 10.3390/ijms21207730] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/14/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023] Open
Abstract
Perinatal stem cells have been regarded as an attractive and available cell source for medical research and clinical trials in recent years. Multiple stem cell types have been identified in the human placenta. Recent advances in knowledge on placental stem cells have revealed that human amniotic epithelial stem cells (hAESCs) have obvious advantages and can be used as a novel potential cell source for cellular therapy and clinical application. hAESCs are known to possess stem-cell-like plasticity, immune-privilege, and paracrine properties. In addition, non-tumorigenicity and a lack of ethical concerns are two major advantages compared with embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). All of the characteristics mentioned above and other additional advantages, including easy accessibility and a non-invasive application procedure, make hAESCs a potential ideal cell type for use in both research and regenerative medicine in the near future. This review article summarizes current knowledge on the characteristics, therapeutic potential, clinical advances and future challenges of hAESCs in detail.
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Affiliation(s)
- Chen Qiu
- MOE Laboratory of Biosystems Homeostasis & Protection and College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, College of Life Sciences, Zhejiang University, Hangzhou 310058, China; (C.Q.); (W.C.)
| | - Zhen Ge
- Institute of Materia Medica, Hangzhou Medical College, Hangzhou 310013, China;
| | - Wenyu Cui
- MOE Laboratory of Biosystems Homeostasis & Protection and College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, College of Life Sciences, Zhejiang University, Hangzhou 310058, China; (C.Q.); (W.C.)
| | - Luyang Yu
- MOE Laboratory of Biosystems Homeostasis & Protection and College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, College of Life Sciences, Zhejiang University, Hangzhou 310058, China; (C.Q.); (W.C.)
- Correspondence: (L.Y.); (J.L.)
| | - Jinying Li
- MOE Laboratory of Biosystems Homeostasis & Protection and College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, College of Life Sciences, Zhejiang University, Hangzhou 310058, China; (C.Q.); (W.C.)
- Correspondence: (L.Y.); (J.L.)
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29
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Platelets Boost Recruitment of CD133 + Bone Marrow Stem Cells to Endothelium and the Rodent Liver-The Role of P-Selectin/PSGL-1 Interactions. Int J Mol Sci 2020; 21:ijms21176431. [PMID: 32899390 PMCID: PMC7504029 DOI: 10.3390/ijms21176431] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 02/06/2023] Open
Abstract
We previously demonstrated that clinical administration of mobilized CD133+ bone marrow stem cells (BMSC) accelerates hepatic regeneration. Here, we investigated the potential of platelets to modulate CD133+BMSC homing to hepatic endothelial cells and sequestration to warm ischemic livers. Modulatory effects of platelets on the adhesion of CD133+BMSC to human and mouse liver-sinusoidal- and micro- endothelial cells (EC) respectively were evaluated in in vitro co-culture systems. CD133+BMSC adhesion to all types of EC were increased in the presence of platelets under shear stress. This platelet effect was mostly diminished by antagonization of P-selectin and its ligand P-Selectin-Glyco-Ligand-1 (PSGL-1). Inhibition of PECAM-1 as well as SDF-1 receptor CXCR4 had no such effect. In a model of the isolated reperfused rat liver subsequent to warm ischemia, the co-infusion of platelets augmented CD133+BMSC homing to the injured liver with heightened transmigration towards the extra sinusoidal space when compared to perfusion conditions without platelets. Extravascular co-localization of CD133+BMSC with hepatocytes was confirmed by confocal microscopy. We demonstrated an enhancing effect of platelets on CD133+BMSC homing to and transmigrating along hepatic EC putatively depending on PSGL-1 and P-selectin. Our insights suggest a new mechanism of platelets to augment stem cell dependent hepatic repair.
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Häussinger D, Kordes C. Space of Disse: a stem cell niche in the liver. Biol Chem 2020; 401:81-95. [PMID: 31318687 DOI: 10.1515/hsz-2019-0283] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 07/08/2019] [Indexed: 02/06/2023]
Abstract
Recent evidence indicates that the plasticity of preexisting hepatocytes and bile duct cells is responsible for the appearance of intermediate progenitor cells capable of restoring liver mass after injury without the need of a stem cell compartment. However, mesenchymal stem cells (MSCs) exist in all organs and are associated with blood vessels which represent their perivascular stem cell niche. MSCs are multipotent and can differentiate into several cell types and are known to support regenerative processes by the release of immunomodulatory and trophic factors. In the liver, the space of Disse constitutes a stem cell niche that harbors stellate cells as liver resident MSCs. This perivascular niche is created by extracellular matrix proteins, sinusoidal endothelial cells, liver parenchymal cells and sympathetic nerve endings and establishes a microenvironment that is suitable to maintain stellate cells and to control their fate. The stem cell niche integrity is important for the behavior of stellate cells in the normal, regenerative, aged and diseased liver. The niche character of the space of Disse may further explain why the liver can become an organ of extra-medullar hematopoiesis and why this organ is frequently prone to tumor metastasis.
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Affiliation(s)
- Dieter Häussinger
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germany
| | - Claus Kordes
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germany
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Magnetic resonance imaging of umbilical cord stem cells labeled with superparamagnetic iron oxide nanoparticles: effects of labelling and transplantation parameters. Sci Rep 2020; 10:13684. [PMID: 32792506 PMCID: PMC7426806 DOI: 10.1038/s41598-020-70291-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 07/28/2020] [Indexed: 12/18/2022] Open
Abstract
Cell tracking with magnetic resonance imaging (MRI) is important for evaluating the biodistribution of transplanted cells. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have emerged as a promising therapeutic tool in regenerative medicine. We examined the UC-MSCs labeled with superparamagnetic (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO) in terms of cell functioning and imaging efficiency in vitro and in vivo. The UC-MSCs were co-incubated with SPIO or USPIO at a concentration of 50 or 100 µg/mL of label. Viability and proliferation were assessed by Trypan blue dye exclusion and MTT assay, respectively. Differentiation (chondrogenesis, osteogenesis, and adipogenesis) was induced to examine the impact of labelling on stemness. For in vitro experiments, we used 7-T MRI to assess the T2 values of phantoms containing various concentrations of cell suspensions. For in vivo experiments, nine neonatal rats were divided into the control, SPIO, and USPIO groups. The UC-MSCs were injected directly into the rat brains. MRI images were obtained immediately and at 7 and 14 days post injection. The UC-MSCs were successfully labeled with SPIO and USPIO after 24 h of incubation. Cell viability was not changed by labelling. Nevertheless, labelling with 100 µg/mL USPIO led to a significant decrease in proliferation. The capacity for differentiation into cartilage was influenced by 100 µg/mL of SPIO. MRI showed that labeled cells exhibited clear hypointense signals, unlike unlabeled control cells. In the USPIO-labeled cells, a significant (P < 0.05) decrease in T2 values (= improved contrast) was observed when compared with the controls and between phantoms containing the fewest and the most cells (0.5 × 106 versus 2.0 × 106 cells/mL). In vivo, the labeled cells were discernible on T2-weighted images at days 0, 7, and 14. The presence of SPIO and USPIO particles at day 14 was confirmed by Prussian blue staining. Microscopy also suggested that the regions occupied by the particles were not as large as the corresponding hypointense areas observed on MRI. Both labels were readily taken up by the UC-MSCs and identified well on MRI. While SPIO and USPIO provide improved results in MRI studies, care must be taken while labelling cells with high concentrations of these agents.
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Advantages of adipose tissue stem cells over CD34 + mobilization to decrease hepatic fibrosis in Wistar rats. Ann Hepatol 2020; 18:620-626. [PMID: 31147180 DOI: 10.1016/j.aohep.2018.12.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 12/04/2018] [Accepted: 11/01/2018] [Indexed: 02/06/2023]
Abstract
INTRODUCTION AND OBJECTIVES Chronic liver inflammation may lead to hepatic cirrhosis, limiting its regenerative capacity. The clinical standard of care is transplantation, although stem cell therapy may be an alternative option. The study aim was to induce endogenous hematopoietic stem cells (HSCs) with granulocyte colony stimulating factor (G-CSF) and/or intravenous administration of adipose tissue-derived mesenchymal stem cells (MSCs) to decrease hepatic fibrosis in an experimental model. MATERIAL AND METHODS A liver fibrosis model was developed with female Wistar rats via multiple intraperitoneal doses of carbon tetrachloride. Three rats were selected to confirm cirrhosis, and the rest were set into experimental groups to evaluate single and combined therapies of G-CSF-stimulated HSC mobilization and intravenous MSC administration. RESULTS Treatment with MSCs and G-CSF significantly improved alanine amino transferase levels, while treatment with G-CSF, MSCs, and G-CSF+MSCs decreased aspartate amino transferase levels. Hepatocyte growth factor (HGF) and interleukin 10 levels increased with MSC treatment. Transforming growth factor β levels were lower with MSC treatment. Interleukin 1β and tumor necrosis factor alpha levels decreased in all treated groups. Histopathology showed that MSCs and G-CSF reduced liver fibrosis from F4 to F2. CONCLUSIONS MSC treatment improves liver function, decreases hepatic fibrosis, and plays an anti-inflammatory role; it promotes HGF levels and increased proliferating cell nuclear antigen when followed by MSC treatment mobilization using G-CSF. When these therapies were combined, however, fibrosis improvement was less evident.
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de Jong IEM, Sutton ME, van den Heuvel MC, Gouw ASH, Porte RJ. Evidence for Recipient-Derived Cells in Peribiliary Glands and Biliary Epithelium of the Large Donor Bile Ducts After Liver Transplantation. Front Cell Dev Biol 2020; 8:693. [PMID: 32850815 PMCID: PMC7419707 DOI: 10.3389/fcell.2020.00693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 07/08/2020] [Indexed: 12/04/2022] Open
Abstract
Introduction Chimerism after orthotopic liver transplantation (OLT) has largely been investigated in intrahepatic cellular constituents. However, little is known about chimerism in the extrahepatic and large intrahepatic bile ducts. Our aim was to evaluate the presence and extent of chimerism after OLT in the peribiliary glands (PBG) and the luminal epithelium of the large donor bile ducts. Methods For this study, we examined six extrahepatic and large intrahepatic bile ducts from livers that were re-transplanted. In all cases there was a sex-mismatch between donor and recipient (female donor organ and male recipient), which allowed to discriminate between donor- and recipient-derived cells. Specimens from female to female transplants were used as negative controls and male to male transplants as positive controls. Fluorescence in situ hybridization (FISH) for Y and X chromosomes was performed and the percentage of XY positive cells was determined among biliary epithelial cells. Immunohistochemistry was used to correlate chimerism with histological features. Results Cholangiocellular chimerism in all studied specimens ranged from 14 to 52%. The degree of chimerism was not associated with biliary damage. Marked chimerism was present at 5 days post-OLT. Ki-67-positivity was detected in 1–8% of the epithelial cells at the time of liver re-transplantation, and this correlated inversely with the degree of chimerism. Conclusion Recipient-derived cholangiocytes are present in the large bile ducts of the donor liver after OLT. The presence of chimerism in the large bile ducts suggests that recipient-derived cells may play a role in biliary regeneration following ischemia-induced injury during OLT.
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Affiliation(s)
- Iris E M de Jong
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.,Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Michael E Sutton
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.,Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Marius C van den Heuvel
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Annette S H Gouw
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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Gu Y, Zheng X, Ji J. Liver cancer stem cells as a hierarchical society: yes or no? Acta Biochim Biophys Sin (Shanghai) 2020; 52:723-735. [PMID: 32490517 DOI: 10.1093/abbs/gmaa050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer stem cells (CSCs) are cells possessing abilities of self-renewal, differentiation, and tumorigenicity in NOD/SCID mice. Based on this definition, multiple cell surface markers (such as CD24, CD133, CD90, and EpCAM) as well as chemical methods are discovered to enrich liver CSCs in the recent decade. Accumulated studies have revealed molecular signatures and signaling pathways involved in regulating different liver CSCs. Among liver CSCs positive for different markers, some molecular features and regulatory pathways are commonly shared, while some are only unique in certain CSC populations. These studies imply that liver CSCs exhibit diverse heterogeneity, while a functional relationship also exists. The aim of this review is to revisit the society of liver CSCs and summarize the common or unique molecular features of known liver CSCs. We hope to call for attention of researchers on the relationship of the liver CSC subgroups and to provide clues on the hierarchical structure of the liver CSC society.
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Affiliation(s)
- Yuanzhuo Gu
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Xin Zheng
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Junfang Ji
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
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Collins DP, Hapke JH, Aravalli RN, Steer CJ. In vitro Differentiation of Human TERT-Transfected Multi-Lineage Progenitor Cells (MLPC) into Immortalized Hepatocyte-Like Cells. Hepat Med 2020; 12:79-92. [PMID: 32607015 PMCID: PMC7295760 DOI: 10.2147/hmer.s245916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 05/26/2020] [Indexed: 12/20/2022] Open
Abstract
Background Research directed towards drug development, metabolism, and liver functions often utilize primary hepatocytes (PH) for preliminary in vitro studies. Variability in the in vitro functionality of PH and the unsuitability of hepatocarcinoma cells for these studies have driven researchers to look to ESC, iPS, and other stem cell types using differentiation protocols to provide more reliable and available cells. This study describes the development of hepatocyte-like cells through the in vitro differentiation of human TERT-immortalized cord blood-derived multi-lineage progenitor cells (MLPC). The E12 clonal cell line derived from polyclonal TERT-transfected cells was used throughout the study. Methods E12 MLPC were subjected to a three-step differentiation protocol using alternating combinations of growth factors, cytokines, and maturational factors. Cells at various stages of differentiation were analyzed for consistency with PH by morphology, immunohistochemistry, urea production, and gene expression. Results E12 MLPC were shown to significantly change morphology with each stage of differentiation. Coincidental with the morphological changes in the cells, immunohistochemistry data documented the differentiation to committed endoderm by the expression of SOX-17 and GATA-4; the progression to committed hepatocyte-like cells by the expression of a large number of markers including α-fetoprotein and albumin; and the final differentiation by the expression of nuclear and cytoplasmic HNF4. Fully differentiated cells demonstrated gene expression, urea production, and immunohistochemistry consistent with PH. A methodology and medium formulation to continuously expand the E12-derived hepatocyte-like cells is described. Conclusion The availability of immortalized hepatocyte-like cell lines could provide a consistent tool for the study of hepatic diseases, drug discovery, and the development of cellular therapies for liver disorders. Utilization of these techniques could provide a basis for the development of bridge therapies for liver failure patients awaiting transplant.
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Affiliation(s)
| | - Joel H Hapke
- Cytomedical Design Group, LLC, Saint Paul, MN 55127, USA
| | - Rajagopal N Aravalli
- Department of Electrical and Computer Engineering, College of Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USA
| | - Clifford J Steer
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.,Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA
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Collins DP, Hapke JH, Aravalli RN, Steer CJ. Development of immortalized human hepatocyte-like hybrid cells by fusion of multi-lineage progenitor cells with primary hepatocytes. PLoS One 2020; 15:e0234002. [PMID: 32497071 PMCID: PMC7272032 DOI: 10.1371/journal.pone.0234002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 05/15/2020] [Indexed: 11/30/2022] Open
Abstract
Human primary hepatocytes (PHs) are critical to studying liver functions, drug metabolism and toxicity. PHs isolated from livers that are unacceptable for transplantation have limited expansion and culture viability in vitro, in addition to rapidly deteriorating enzymatic functions. The unsuitability of immortalized hepato-carcinoma cell lines for this function has prompted studies to develop hepatocyte-like cells from alternative sources like ESC, iPS, and other stem cell types using differentiation protocols. This study describes a novel technique to produce expandable and functional hepatocyte-like cells from the fusion of an immortalized human umbilical cord blood derived cell line (E12 MLPC) to normal human primary hepatocytes. Multi-lineage progenitor cells (MLPC) comprise a small subset of mesenchymal-like cells isolated from human umbilical cord blood. MLPC are distinguishable from other mesenchymal-like cells by their extended expansion capacity (up to 80 cell doublings before senescence) and the ability to be differentiated into cells representative of endo-, meso- and ectodermal origins. Transfection of MLPC with the gene for telomerase reverse transcriptase (TERT) resulted in clonal cell lines that were capable of differentiation to different cellular outcomes while maintaining their functional immortality. A methodology for the development of immortalized hepatocyte-like hybrid cells by the in vitro fusion of human MLPC with normal human primary hepatocytes is reported. The resultant hybrid cells exhibited homology with hepatocytes by morphology, immunohistochemistry, urea and albumin production and gene expression. A medium that allows stable long-term expansion of hepatocyte-like fusion cells is described.
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Affiliation(s)
| | - Joel H. Hapke
- CMDG, LLC, Saint Paul, Minnesota, United States of America
| | - Rajagopal N. Aravalli
- Department of Electrical and Computer Engineering, College of Science and Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Clifford J. Steer
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
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Multi-Spheroid-Loaded Human Acellular Dermal Matrix Carrier Preserves Its Spheroid Shape and Improves In Vivo Adipose-Derived Stem Cell Delivery and Engraftment. Tissue Eng Regen Med 2020; 17:271-283. [PMID: 32314311 DOI: 10.1007/s13770-020-00252-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/09/2020] [Accepted: 03/15/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Current in vivo adult stem cell delivery presents limited clinical effects due to poor engraftment and survival. To overcome current challenges in cell delivery and promote surgical cell delivery for soft tissue repair, a multi-spheroid-loaded thin sectioned acellular dermal matrix (tsADM) carrier which preserves loaded spheroids' three-dimensional (3D) structure, was developed. METHODS Adipose-derived stem cells (ASCs) were used for spheroid delivery. After generating spheroids in 3D cell culture dishes, spheroid plasticity and survival in-between coverslips were evaluated. Spheroids were loaded onto tsADM, their shape changes were followed up for 14 days, and then imaged. Spheroid adhesion stability to tsADM against shear stress was also evaluated. Finally, cell delivery efficacy was compared with cell-seeded tsADM by in vivo implantation and histological evaluation. RESULTS Spheroids withstood cyclic compression stress and maintained their 3D shape without fusion after 48 h of culture in-between coverslips. Cell survival improved when spheroids were cultured on tsADM in-between the coverslips. Spheroid-loaded tsADM with coverslips maintained their spheroid outline for 14 days of culture whereas without coverslips, the group lost their outline due to spreading after 4 days in culture. Spheroids loaded onto tsADMs were more stable after six rather than 3 days in culture. Spheroid-loaded tsADMs showed about a 2.96-fold higher ASCs transplantation efficacy than cell-seeded tsADMs after 2 weeks of in vivo transplantation. CONCLUSION These results indicate that transplantation of spheroid-loaded tsADMs significantly improved cell delivery. These findings suggest that a combined approach with other cells, drugs, and nanoparticles may improve cell delivery and therapeutic efficacy.
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Lee JY, Hong SH. Hematopoietic Stem Cells and Their Roles in Tissue Regeneration. Int J Stem Cells 2020; 13:1-12. [PMID: 31887851 PMCID: PMC7119209 DOI: 10.15283/ijsc19127] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 11/18/2019] [Accepted: 12/01/2019] [Indexed: 12/22/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are regarded as one of essential cell sources for treating regenerative diseases. Among many stem cells, the feasibility of using adult-derived hematopoietic stem cells in therapeutic approaches is very diverse, and is unarguably regarded as an important cell source in stem cell biology. So far, many investigators are exploring HSCs and modified HSCs for use in clinical and basic science. In the present review, we briefly summarized HSCs and their application in pathophysiologic conditions, including non-hematopoietic tissue regeneration as well as blood disorders. HSCs and HSCs-derived progenitors are promising cell sources in regenerative medicine and their contributions can be properly applied to treat pathophysiologic conditions. Among many adult stem cells, HSCs are a powerful tool to treat patients with diseases such as hematologic malignancies and liver disease. Since HSCs can be differentiated into diverse progenitors including endothelial progenitors, they may be useful for constructing strategies for effective therapy.
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Affiliation(s)
- Ji Yoon Lee
- CHA Advanced Research Institute, CHA University, Seongnam, Korea
| | - Seok-Ho Hong
- Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Korea
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The Cancer Stem Cell in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12030684. [PMID: 32183251 PMCID: PMC7140091 DOI: 10.3390/cancers12030684] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/11/2020] [Accepted: 03/12/2020] [Indexed: 12/11/2022] Open
Abstract
The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma.
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Tricot T, De Boeck J, Verfaillie C. Alternative Cell Sources for Liver Parenchyma Repopulation: Where Do We Stand? Cells 2020; 9:E566. [PMID: 32121068 PMCID: PMC7140465 DOI: 10.3390/cells9030566] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/20/2020] [Accepted: 02/22/2020] [Indexed: 12/28/2022] Open
Abstract
Acute and chronic liver failure is a highly prevalent medical condition with high morbidity and mortality. Currently, the therapy is orthotopic liver transplantation. However, in some instances, chiefly in the setting of metabolic diseases, transplantation of individual cells, specifically functional hepatocytes, can be an acceptable alternative. The gold standard for this therapy is the use of primary human hepatocytes, isolated from livers that are not suitable for whole organ transplantations. Unfortunately, primary human hepatocytes are scarcely available, which has led to the evaluation of alternative sources of functional hepatocytes. In this review, we will compare the ability of most of these candidate alternative cell sources to engraft and repopulate the liver of preclinical animal models with the repopulation ability found with primary human hepatocytes. We will discuss the current shortcomings of the different cell types, and some of the next steps that we believe need to be taken to create alternative hepatocyte progeny capable of regenerating the failing liver.
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Bergeron L, Busuttil V, Botto JM. Multipotentiality of skin-derived precursors: application to the regeneration of skin and other tissues. Int J Cosmet Sci 2020; 42:5-15. [PMID: 31612512 DOI: 10.1111/ics.12587] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 10/12/2019] [Indexed: 12/13/2022]
Abstract
Skin-derived precursors (SKPs) have been described as multipotent dermal precursors. Here, we provide a review of the breadth and depth of scientific literature and studies regarding SKPs, accounting for a large number of scientific publications. Interestingly, these progenitors can be isolated from embryonic and adult skin, as well as from a population of dermal cells cultured in vitro in monolayer. Gathering information from different authors, this review explores different aspects of the SKP theme, such as the potential distinct origins of SKPs in rodents and in humans, and also their ability to differentiate in vitro and in vivo into multiple lineages of different progeny. This remarkable capacity makes SKPs an interesting endogenous source of precursors to explore in the framework of experimental and therapeutic applications in different domains. SKPs are not only involved in the skin's dermal maintenance and support as well as wound healing, but also in hair follicle morphogenesis. This review points out the interests of future researches on SKPs for innovative perspectives that may be helpful in many different types of scientific and medical domains.
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Affiliation(s)
- L Bergeron
- Ashland Specialties France, Global Skin Research Center, 655, route du Pin Montard, 06904, Sophia Antipolis, France
| | - V Busuttil
- Ashland Specialties France, Global Skin Research Center, 655, route du Pin Montard, 06904, Sophia Antipolis, France
| | - J-M Botto
- Ashland Specialties France, Global Skin Research Center, 655, route du Pin Montard, 06904, Sophia Antipolis, France
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Bartold M, Gronthos S, Haynes D, Ivanovski S. Mesenchymal stem cells and biologic factors leading to bone formation. J Clin Periodontol 2019; 46 Suppl 21:12-32. [PMID: 30624807 DOI: 10.1111/jcpe.13053] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 09/23/2018] [Accepted: 10/26/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Physiological bone formation and bone regeneration occurring during bone repair can be considered distinct but similar processes. Mesenchymal stem cells (MSC) and associated biologic factors are crucial to both bone formation and bone regeneration. AIM To perform a narrative review of the current literature regarding the role of MSC and biologic factors in bone formation with the aim of discussing the clinical relevance of in vitro and in vivo animal studies. METHODS The literature was searched for studies on MSC and biologic factors associated with the formation of bone in the mandible and maxilla. The search specifically targeted studies on key aspects of how stem cells and biologic factors are important in bone formation and how this might be relevant to bone regeneration. The results are summarized in a narrative review format. RESULTS Different types of MSC and many biologic factors are associated with bone formation in the maxilla and mandible. CONCLUSION Bone formation and regeneration involve very complex and highly regulated cellular and molecular processes. By studying these processes, new clinical opportunities will arise for therapeutic bone regenerative treatments.
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Affiliation(s)
- Mark Bartold
- School of Dentistry, University of Adelaide, Adelaide, SA, Australia
| | - Stan Gronthos
- Mesenchymal Stem Cell Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - David Haynes
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia
| | - Saso Ivanovski
- School of Dentistry, University of Queensland, Brisbane, Qld, Australia
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Generation of functional hepatocyte-like cells from human bone marrow mesenchymal stem cells by overexpression of transcription factor HNF4α and FOXA2. Hepatobiliary Pancreat Dis Int 2019; 18:546-556. [PMID: 31230960 DOI: 10.1016/j.hbpd.2019.03.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 03/05/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Our previous study showed that overexpression of hepatocyte nuclear factor 4α (HNF4α) could directly promote mesenchymal stem cells (MSCs) to differentiate into hepatocyte-like cells. However, the efficiency of hepatic differentiation remains low. The purpose of our study was to establish an MSC cell line that overexpressed HNF4α and FOXA2 genes to obtain an increased hepatic differentiation efficiency and hepatocyte-like cells with more mature hepatocyte functions. METHODS Successful establishment of high-level HNF4α and FOXA2 co-overexpression in human induced hepatocyte-like cells (hiHep cells) was verified by flow cytometry, immunofluorescence and RT-PCR. Measurements of albumin (ALB), urea, glucose, indocyanine green (ICG) uptake and release, cytochrome P450 (CYP) activity and gene expression were used to analyze mature hepatic functions of hiHep cells. RESULTS hiHep cells efficiently express HNF4α and FOXA2 genes and proteins, exhibit typical epithelial morphology and acquire mature hepatocyte-like cell functions, including ALB secretion, urea production, ICG uptake and release, and glycogen storage. hiHep cells can be activated by CYP inducers. The percentage of both ALB and α-1-antitrypsin (AAT)-positive cells was approximately 72.6%. The expression levels of hepatocyte-specific genes (ALB, AAT, and CYP1A1) and liver drug transport-related genes (ABCB1, ABCG2, and SLC22A18) in hiHep cells were significantly higher than those in MSCs-Vector cells. The hiHep cells did not form tumors after subcutaneous xenograft in BALB/c nude mice after 2 months. CONCLUSION This study provides an accessible, feasible and efficient strategy to generate hiHep cells from MSCs.
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Teng YD. Functional multipotency of stem cells: Biological traits gleaned from neural progeny studies. Semin Cell Dev Biol 2019; 95:74-83. [DOI: 10.1016/j.semcdb.2019.02.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 01/24/2019] [Accepted: 02/21/2019] [Indexed: 12/28/2022]
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Khalil S, Ariel Gru A, Saavedra AP. Cutaneous extramedullary haematopoiesis: Implications in human disease and treatment. Exp Dermatol 2019; 28:1201-1209. [DOI: 10.1111/exd.14013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 06/26/2019] [Accepted: 07/11/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Shadi Khalil
- Department of Dermatology University of Virginia School of Medicine Charlottesville Virginia
| | - Alejandro Ariel Gru
- Department of Pathology University of Virginia School of Medicine Charlottesville Virginia
| | - Arturo P. Saavedra
- Department of Dermatology University of Virginia School of Medicine Charlottesville Virginia
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47
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Zhou M, Shen L, Qiao Y, Sun Z. Inducing differentiation of human urine-derived stem cells into hepatocyte-like cells by coculturing with human hepatocyte L02 cells. J Cell Biochem 2019; 121:566-573. [PMID: 31407401 DOI: 10.1002/jcb.29301] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 06/27/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To investigate the possibility of inducing differentiation of human urine-derived stem cells (hUSCs) into hepatocyte-like cells by coculturing with human hepatocyte L02 cells in vitro. METHODS HUSCs were isolated from fresh urine samples collected from healthy adult volunteers by centrifugation. Cells were observed under an inverted phase contrast microscope, and proliferative activity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Stem cell surface markers were detected by flow cytometry. HUSCs were induced to differentiate into hepatocyte-like cells by coculturing with human hepatocyte L02 cells, which were confirmed by cellular morphology, messenger RNA expression of albumin (ALB), α-fetoprotein (AFP) and hepatocyte cytochrome P450 (CYP450) analyzed with quantitative reverse transcription polymerase chain reaction and the expression of glycogen detected by glycogen staining kits at 5, 10, and 15 days after coculturing. RESULTS HUSCs from urine were successfully isolated and cultured in vitro. At passages 3, the growth curve of hUSCs was S-shaped with good proliferation activity. Mesenchymal stem cell surface markers CD44 and CD90 were detected positive by flow cytometry. CD31 for endothelial cells and CD34 for hematopoietic stem cell markers were not detected. HUSCs gained the cellular morphology and function of hepatocyte cells including higher expression of several hepatocyte-specific genes such as ALB and some CYP450, lower expression of AFP and positive glycogen expression (P < .05) in coculturing with human hepatocyte L02 cells for 10-15d. CONCLUSIONS HUSCs can be induced to differentiate into hepatocyte-like cells by coculturing with human hepatocyte L02 cells for a certain number of days.
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Affiliation(s)
- Ming Zhou
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Liangliang Shen
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yinggu Qiao
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Zhenxiao Sun
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
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Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal Stem Cells for Regenerative Medicine. Cells 2019; 8:E886. [PMID: 31412678 PMCID: PMC6721852 DOI: 10.3390/cells8080886] [Citation(s) in RCA: 699] [Impact Index Per Article: 116.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/05/2019] [Accepted: 08/06/2019] [Indexed: 02/06/2023] Open
Abstract
In recent decades, the biomedical applications of mesenchymal stem cells (MSCs) have attracted increasing attention. MSCs are easily extracted from the bone marrow, fat, and synovium, and differentiate into various cell lineages according to the requirements of specific biomedical applications. As MSCs do not express significant histocompatibility complexes and immune stimulating molecules, they are not detected by immune surveillance and do not lead to graft rejection after transplantation. These properties make them competent biomedical candidates, especially in tissue engineering. We present a brief overview of MSC extraction methods and subsequent potential for differentiation, and a comprehensive overview of their preclinical and clinical applications in regenerative medicine, and discuss future challenges.
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Affiliation(s)
- Yu Han
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
| | - Xuezhou Li
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
| | - Yanbo Zhang
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun 130033, China.
| | - Yuping Han
- Department of Urology, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun 130033, China.
| | - Fei Chang
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China.
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
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Esmaeilzadeh A, Ommati H, Kooshyar MM, Jarahi L, Akhavan Rezayat K, Saberi S, Vosough M, Ghassemi A. Autologous Bone Marrow Stem Cell Transplantation in Liver Cirrhosis after Correcting Nutritional Anomalies, A Controlled Clinical Study. CELL JOURNAL 2019; 21:268-273. [PMID: 31210432 PMCID: PMC6582418 DOI: 10.22074/cellj.2019.6108] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Accepted: 10/08/2018] [Indexed: 01/18/2023]
Abstract
Objective Liver transplantation is the gold standard approach for decompensated liver cirrhosis. In recent years, stem
cell therapy has raised hopes that adjusting some clinical and laboratory parameters could lead to successful treatments
for this disease. Cirrhotic patients may have multiple systemic abnormalities in peripheral blood and irregular cell
populations in bone marrow (BM). Correcting these abnormalities before BM aspiration may improve the effectiveness
of cell-based therapy of liver cirrhosis.
Materials and Methods In this controlled clinical trial study, 20 patients with decompensated liver cirrhosis were enrolled.
Patients were randomly assigned to control and experimental groups. Blood samples were obtained to measure vitamin
B12, folate, serum iron, total iron bonding capacity (TIBC) and ferritin before any intervention. Furthermore, the iron
storage and fibrosis level in BM biopsies, as well as the percentage of different cell populations, were evaluated. Prior
to cell isolation for transplantation, we performed palliative supplement therapy followed by a correction of nutritional
deficiencies. Mononuclear cells (MNCs) were then isolated from BM aspirates and transfused through peripheral vein in
patients in the experimental group. The model of end-stage liver disease (MELD) score, The international normalized ratio
(INR), serum albumin and bilirubin levels were assessed at 0 (baseline), 3 and 6 months after cell transplantation.
Results The MELD score (P=0.0001), INR (P=0.012), bilirubin (P<0.0001) and total albumin (P<0.0001) levels
improved significantly in the experimental group after cell transplantation compared to the baseline and control groups.
Moreover, the increase in serum albumin levels of patients in the experimental group was statistically significant 6
months after transplantation.
Conclusion We have successfully improved the conditions of preparing -BM-derived stem cells for transplantation.
Although these cells are relatively safe and have been shown to improve some clinical signs and symptoms temporarily,
there need to be more basic studies regarding the preparation steps for effective clinical use (Registration number:
IRCT2014091919217N1).
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Affiliation(s)
- Abbas Esmaeilzadeh
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Gastroenterology and Hepatology Research Center, Mashhad, Iran
| | - Homeira Ommati
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Gastroenterology and Hepatology Research Center, Mashhad, Iran
| | - Mohammad Mahdi Kooshyar
- Department of Hematology and Oncology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Lida Jarahi
- Department of Community Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kambiz Akhavan Rezayat
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Gastroenterology and Hepatology Research Center, Mashhad, Iran
| | - Samaneh Saberi
- HPGC Group, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Biomedicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.Electronic Address:,
| | - Ali Ghassemi
- Department of Pediatric Hematology and Oncology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.Electronic Address:
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Oh JE, Choi OK, Park HS, Jung HS, Ryu SJ, Lee YD, Lee SA, Chung SS, Choi EY, Lee DS, Gho YS, Lee H, Park KS. Direct differentiation of bone marrow mononucleated cells into insulin producing cells using pancreatic β-cell-derived components. Sci Rep 2019; 9:5343. [PMID: 30926860 PMCID: PMC6441031 DOI: 10.1038/s41598-019-41823-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 03/04/2019] [Indexed: 12/31/2022] Open
Abstract
Transplantation of stem cell-derived insulin producing cells (IPCs) has been proposed as an alternative to islet transplantation for the treatment of diabetes mellitus. However, current IPC differentiation protocols are focused on generating functional cells from the pluripotent stem cells and tend to rely on multistep, long-term exposure to various exogenous factors. In this study, we addressed the observation that under stress, pancreatic β-cells release essential components that direct the differentiation of the bone marrow nucleated cells (BMNCs) into IPCs. Without any supplementation with known differentiation-inducing factors, IPCs can be generated from BMNCs by in vitro priming for 6 days with conditioned media (CM) from the β-cells. In vitro primed BMNCs expressed the β-cell-specific transcription factors, as well as insulin, and improved hyperglycemia and glucose intolerance after transplantation into the streptozotocin-induced diabetic mice. Furthermore, we have found that components of the CM which trigger the differentiation were enclosed by or integrated into micro particles (MPs), rather than being secreted as soluble factors. Identification of these differentiation-directing factors might enable us to develop novel technologies required for the production of clinically applicable IPCs.
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Affiliation(s)
- Ju Eun Oh
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080, Republic of Korea
| | - Ok Kyung Choi
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Ho Seon Park
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Hye Seung Jung
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Su Jeong Ryu
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Yong Deok Lee
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Seung-Ah Lee
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080, Republic of Korea
| | - Sung Soo Chung
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Eun Young Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Dong-Sup Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Yong Song Gho
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, 37673, Republic of Korea
| | - Hakmo Lee
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. .,Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, 05368, Republic of Korea.
| | - Kyong Soo Park
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. .,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080, Republic of Korea. .,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
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