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Fetal, Perinatal, and Adult-Derived Allogenic Stem Cells for the Treatment...
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Fetal, Perinatal, and Adult-Derived Allogenic Stem Cells for the Treatment of Liver Diseases: A Therapeutic Approach in Support of or as an Alternative to Solid Organ Transplantation

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 22658

Special Issue Editors

Dr. Maria G. Roubelakis

E-Mail Website
Guest Editor
Laboratory of Biology, Medical School of Athens, National and Kapodistrian University of Athens, 75, Mikras Asias st, 11527 Athens, Greece
Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 4, Soranou Efessiou st, 11527 Athens, Greece
Interests: stem cell biology; regenerative medicine, fetal stem cells; mesenchymal stem/stromal cells; differentiation; acute liver failure; animal models; cell therapy
Prof. Dr. Roberto Gramignoli

E-Mail Website
Guest Editor
Karolinska Institutet Dept. of Laboratory Medicine Division of Pathology, plan 8 (room 83116) Alfred nobel alle 8, Huddinge SE-141 52 Stockholms Land, Sweden
Interests: cell-based therapy; regenerative medicine; hepatocyte; perinatal stem cells; placenta; ips; liver; metabolic disease; cryopreservation; cell isolation

Special Issue Information

Dear Colleagues,

Given your research and expertise in this area of research, we would like to invite you to contribute an article for a Special Issue on “Fetal, Perinatal. and Adult-Derived Allogenic Stem Cells for the Treatment of Liver Diseases: A Therapeutic Approach in Support of or as an Alternative to Solid Organ Transplantation” in the Cells journal.

Cells (IF 6.6) publishes high-quality frontier manuscripts, drug clinical trial studies, and guest-edited issues on all aspects of basic research on cell biology and clinical therapy.

A short description of the Special Issue is included below:

“Fetal, Perinatal. and Adult-Derived Allogenic Stem Cells for the Treatment of Liver Diseases: A Therapeutic Approach in Support of or as an Alternative to Solid Organ Transplantation”

Liver dysfunctions are classified into acute and chronic diseases, which comprise a heterogeneous group of pathological features and a high mortality rate. Liver transplantation remains the gold standard therapy for most liver diseases, with concomitant limitations related to donor organ shortage and life-long immunosuppressive therapy. Thirty years of experimental cell transplantation have consolidated and proved the concept where allogenic infusion of a relatively small number of cells can offer supportive or rescue therapy able to overcome several limitations based on solid organ or tissue implantation. Functional and mature hepatocytes have been transplanted to replace damaged tissue or provide missing function. Metabolic pathways frequently altered or impaired in inborn errors of metabolism have been analyzed and restored using both intact cell implantation and gene therapies or enzyme replacement therapies.

The transplantation of pluripotent and multipotent stem cells is aimed at supporting innate regeneration or providing allogenic mature cells. Additional attempts have focused on replacing the missing activity with allogenic progenitor/fetal cells. Furthermore, several cellular approaches have recently been described in support of reverse fibrosis or inflammation via the injection of cellular derivatives (i.e., secretome). Similar cellular treatments have also been proposed in support of solid organ transplantation, where allogenic rejection can be prevented or contained by third-party allogenic cells or the stem-cell-derived secretome.

Finally, a series of promising studies have recently described using perinatal or fetal mesenchymal stem/progenitor cells (MSCs) in support of acute and congenital liver disorders. Such a relatively new source of stem cells comprises the umbilical cord, amniotic fluid, amniotic membrane, or placenta, which are normally discarded after birth. Ethical concerns regarding the isolation of MSCs from these sources are minimized. Perinatal stem cells are characterized by important immune-modulatory and anti-inflammatory features, as well as embryonic and multipotent characteristics.

In the proposed Special Issue, we aim to collect and offer insights into innovative or established cellular treatments for liver disorders. Particular attention will be paid to the biology and main aspects of pluripotent or multipotent stem cells, derived from various sources, and the cellular and molecular mechanisms by which these cells are involved in therapeutic potential. We welcome submissions where, in addition to or as an alternative to intact cell transplantation, cellular mediators as secreted vesicles or soluble molecules have been implemented to support cell or tissue regeneration.

Dr. Maria G. Roubelakis
Dr. Roberto Gramignoli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Fetal stem cells
  • Placenta stem cells
  • Perinatal stem cells
  • Adult or somatic stem cells
  • Mesenchymal stem/stromal Cells
  • Secretome
  • Extracellular vesicles
  • Acute hepatic failure
  • Chronic liver failure
  • Congenital liver failure
  • Metabolic disorders
  • Immune-modulatory treatment
  • Fibrosis
  • Inflammation

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Published Papers (6 papers)

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Research

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23 pages, 5960 KiB  
Article
In Vitro Differentiation of Human Amniotic Epithelial Cells into Hepatocyte-like Cells
by Marcin Michalik, Patrycja Wieczorek and Piotr Czekaj
Cells 2022, 11(14), 2138; https://doi.org/10.3390/cells11142138 - 7 Jul 2022
Cited by 2 | Viewed by 2831
Abstract
Human amniotic epithelial cells (hAECs) represent an interesting clinical alternative to human embryonic (hESCs) and induced pluripotent (hiPSCs) stem cells in regenerative medicine. The potential of hAECs can be enhanced ex vivo by their partial pre-differentiation. The aim of this study was to [...] Read more.
Human amniotic epithelial cells (hAECs) represent an interesting clinical alternative to human embryonic (hESCs) and induced pluripotent (hiPSCs) stem cells in regenerative medicine. The potential of hAECs can be enhanced ex vivo by their partial pre-differentiation. The aim of this study was to evaluate the effectiveness of 18-day differentiation of hAECs into endodermal cells, hepatic precursor cells, and cells showing functional features of hepatocytes using culture media supplemented with high (100 ng/mL) concentrations of EGF or HGF. The cells obtained after differentiation showed changes in morphology and increased expression of AFP, ALB, CYP3A4, CYP3A7, and GSTP1 genes. HGF was more effective than EGF in increasing the expression of liver-specific genes in hAECs. However, EGF stimulated the differentiation process more efficiently and yielded more hepatocyte-like cells capable of synthesizing α-fetoprotein during differentiation. Additionally, after 18 days, GST transferases, albumin, and CYP P450s, which proved their partial functionality, were expressed. In summary, HGF and EGF at a dose of 100 ng/mL can be successfully used to obtain hepatocyte-like cells between days 7 and 18 of hAEC differentiation. However, the effectiveness of this process is lower compared with hiPSC differentiation; therefore, optimization of the composition of the medium requires further research. Full article
(This article belongs to the Special Issue Fetal, Perinatal, and Adult-Derived Allogenic Stem Cells for the Treatment of Liver Diseases: A Therapeutic Approach in Support of or as an Alternative to Solid Organ Transplantation)
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18 pages, 2895 KiB  
Article
Human Amnion-Derived Mesenchymal Stromal/Stem Cells Pre-Conditioning Inhibits Inflammation and Apoptosis of Immune and Parenchymal Cells in an In Vitro Model of Liver Ischemia/Reperfusion
by Giovanni Zito, Vitale Miceli, Claudia Carcione, Rosalia Busà, Matteo Bulati, Alessia Gallo, Gioacchin Iannolo, Duilio Pagano and Pier Giulio Conaldi
Cells 2022, 11(4), 709; https://doi.org/10.3390/cells11040709 - 17 Feb 2022
Cited by 16 | Viewed by 3053
Abstract
Ischemia/reperfusion injury (IRI) represents one of the leading causes of primary non-function acute liver transplantation failure. IRI, generated by an interruption of organ blood flow and the subsequent restoration upon transplant, i.e., reperfusion, generates the activation of an inflammatory cascade from the resident [...] Read more.
Ischemia/reperfusion injury (IRI) represents one of the leading causes of primary non-function acute liver transplantation failure. IRI, generated by an interruption of organ blood flow and the subsequent restoration upon transplant, i.e., reperfusion, generates the activation of an inflammatory cascade from the resident Kupffer cells, leading first to neutrophils recruitment and second to apoptosis of the parenchyma. Recently, human mesenchymal stromal/stem cells (hMSCs) and derivatives have been implemented for reducing the damage induced by IRI. Interestingly, sparse data in the literature have described the use of human amnion-derived MSCs (hAMSCs) and, more importantly, no evidence regarding hMSCs priming on liver IRI have been described yet. Thus, our study focused on the definition of an in vitro model of liver IRI to test the effect of primed hAMSCs to reduce IRI damage on immune and hepatic cells. We found that the IFNγ pre-treatment and 3D culture of hAMSCs strongly reduced inflammation induced by M1-differentiated macrophages. Furthermore, primed hAMSCs significantly inhibited parenchymal apoptosis at early timepoints of reperfusion by blocking the activation of caspase 3/7. All together, these data demonstrate that hAMSCs priming significantly overcomes IRI effects in vitro by engaging the possibility of defining the molecular pathways involved in this process. Full article
(This article belongs to the Special Issue Fetal, Perinatal, and Adult-Derived Allogenic Stem Cells for the Treatment of Liver Diseases: A Therapeutic Approach in Support of or as an Alternative to Solid Organ Transplantation)
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Review

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23 pages, 340 KiB  
Review
Cellular Therapies in Pediatric Liver Diseases
by Sunitha Vimalesvaran, Jessica Nulty and Anil Dhawan
Cells 2022, 11(16), 2483; https://doi.org/10.3390/cells11162483 - 10 Aug 2022
Cited by 3 | Viewed by 1992
Abstract
Liver transplantation is the gold standard for the treatment of pediatric end-stage liver disease and liver based metabolic disorders. Although liver transplant is successful, its wider application is limited by shortage of donor organs, surgical complications, need for life long immunosuppressive medication and [...] Read more.
Liver transplantation is the gold standard for the treatment of pediatric end-stage liver disease and liver based metabolic disorders. Although liver transplant is successful, its wider application is limited by shortage of donor organs, surgical complications, need for life long immunosuppressive medication and its associated complications. Cellular therapies such as hepatocytes and mesenchymal stromal cells (MSCs) are currently emerging as an attractive alternative to liver transplantation. The aim of this review is to present the existing world experience in hepatocyte and MSC transplantation and the potential for future effective applications of these modalities of treatment. Full article
(This article belongs to the Special Issue Fetal, Perinatal, and Adult-Derived Allogenic Stem Cells for the Treatment of Liver Diseases: A Therapeutic Approach in Support of or as an Alternative to Solid Organ Transplantation)
23 pages, 1464 KiB  
Review
Liver Regeneration by Hematopoietic Stem Cells: Have We Reached the End of the Road?
by Elena Konstantina Siapati, Maria G. Roubelakis and George Vassilopoulos
Cells 2022, 11(15), 2312; https://doi.org/10.3390/cells11152312 - 27 Jul 2022
Cited by 8 | Viewed by 5376
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Fetal, Perinatal, and Adult-Derived Allogenic Stem Cells for the Treatment of Liver Diseases: A Therapeutic Approach in Support of or as an Alternative to Solid Organ Transplantation)
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20 pages, 1227 KiB  
Review
The Potential Clinical Use of Stem/Progenitor Cells and Organoids in Liver Diseases
by Christina Nikokiraki, Adriana Psaraki and Maria G. Roubelakis
Cells 2022, 11(9), 1410; https://doi.org/10.3390/cells11091410 - 21 Apr 2022
Cited by 13 | Viewed by 4180
Abstract
The liver represents the most important metabolic organ of the human body. It is evident that an imbalance of liver function can lead to several pathological conditions, known as liver failure. Orthotropic liver transplantation (OLT) is currently the most effective and established treatment [...] Read more.
The liver represents the most important metabolic organ of the human body. It is evident that an imbalance of liver function can lead to several pathological conditions, known as liver failure. Orthotropic liver transplantation (OLT) is currently the most effective and established treatment for end-stage liver diseases and acute liver failure (ALF). Due to several limitations, stem-cell-based therapies are currently being developed as alternative solutions. Stem cells or progenitor cells derived from various sources have emerged as an alternative source of hepatic regeneration. Therefore, hematopoietic stem cells (HSCs), mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are also known to differentiate into hepatocyte-like cells (HPLCs) and liver progenitor cells (LPCs) that can be used in preclinical or clinical studies of liver disease. Furthermore, these cells have been shown to be effective in the development of liver organoids that can be used for disease modeling, drug testing and regenerative medicine. In this review, we aim to discuss the characteristics of stem-cell-based therapies for liver diseases and present the current status and future prospects of using HLCs, LPCs or liver organoids in clinical trials. Full article
(This article belongs to the Special Issue Fetal, Perinatal, and Adult-Derived Allogenic Stem Cells for the Treatment of Liver Diseases: A Therapeutic Approach in Support of or as an Alternative to Solid Organ Transplantation)
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18 pages, 1041 KiB  
Review
Extraembryonic Mesenchymal Stromal/Stem Cells in Liver Diseases: A Critical Revision of Promising Advanced Therapy Medicinal Products
by Mohammad Amin Shahrbaf, Masoumeh Nouri, Morteza Zarrabi, Roberto Gramignoli and Massoud Vosough
Cells 2022, 11(7), 1074; https://doi.org/10.3390/cells11071074 - 23 Mar 2022
Cited by 6 | Viewed by 4085
Abstract
Liver disorders have been increasing globally in recent years. These diseases are associated with high morbidity and mortality rates and impose high care costs on the health system. Acute liver failure, chronic and congenital liver diseases, as well as hepatocellular carcinoma have been [...] Read more.
Liver disorders have been increasing globally in recent years. These diseases are associated with high morbidity and mortality rates and impose high care costs on the health system. Acute liver failure, chronic and congenital liver diseases, as well as hepatocellular carcinoma have been limitedly treated by whole organ transplantation so far. But novel treatments for liver disorders using cell-based approaches have emerged in recent years. Extra-embryonic tissues, including umbilical cord, amnion membrane, and chorion plate, contain multipotent stem cells. The pre-sent manuscript discusses potential application of extraembryonic mesenchymal stromal/stem cells, focusing on the management of liver diseases. Extra-embryonic MSC are characterized by robust and constitutive anti-inflammatory and anti-fibrotic properties, indicating as therapeutic agents for inflammatory conditions such as liver fibrosis or advanced cirrhosis, as well as chronic inflammatory settings or deranged immune responses. Full article
(This article belongs to the Special Issue Fetal, Perinatal, and Adult-Derived Allogenic Stem Cells for the Treatment of Liver Diseases: A Therapeutic Approach in Support of or as an Alternative to Solid Organ Transplantation)
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