Stem Cells as a Model of Study of SARS-CoV-2 and COVID-19: A Systematic Review of the Literature

Background. The SARS-CoV-2 virus is the cause of the latest pandemic of the 21st century; it is responsible for the development of COVID-19. Within the multiple study models for both the biology and the treatment of SARS-CoV-2, the use of stem cells has been proposed because of their ability to increase the immune response and to repair tissue. Therefore, the objective of this review is to evaluate the role of stem cells against SARS-CoV-2 and COVID-19 in order to identify their potential as a study model and as a possible therapeutic source against tissue damage caused by this virus. Therefore, the following research question was established: What is the role of stem cells in the study of SARS-CoV-2 and the treatment of COVID-19? Materials and Methods. A search was carried out in the electronic databases of PUBMED, Scopus, and ScienceDirect. The following keywords were used: “SARS-CoV-2,” “COVID-19,” and “STEM CELL,” plus independent search strategies with the Boolean operators “OR” and “AND.” The identified reports were those whose main objective was the study of stem cells in relation to SARS-CoV-2 or COVID-19. For the development of this study, the following inclusion criteria were taken into account: studies whose main objective was the study of stem cells in relation to SARS-CoV-2 or COVID-19 and clinical case studies, case reports, clinical trials, pilot studies, in vitro, or in vivo studies. For assessment of the risk of bias for in vitro studies, the SciRAP tool was used. The data collected for each type of study, clinical or in vitro, were analyzed with descriptive statistics using the SPSS V.22 program. Results. Of the total of studies included ( n = 39 ), 22 corresponded to in vitro investigations and 17 to human studies (clinical cases ( n = 9 ), case series ( n = 2 ), pilot clinical trials ( n = 5 ), clinical trials ( n = 1 )). In vitro studies that induced pluripotent stem cells were the most used ( n = 12 ), and in clinical studies, the umbilical stem cells derived were the most reported ( n = 11 ). The mean age of the study subjects was 58.3 years. After the application of stem cell therapy, the follow-up period was 8 days minimum and 90 days maximum. Discussion. The mechanism by which the virus enters the cell is through protein “S,” located on the surface of the membrane, by recognizing the ACE2 receptor located on the target cell. The evidence that the expression of ACE2 and TMPRSS2 in stem cells indicates that stem cells from bone marrow and amniotic fluid have very little expression. This shows that stem cell has a low risk of infection with SARS-CoV-2. Conclusion. The use of stem cells is a highly relevant therapeutic option. It has been shown in both in vitro studies and clinical trials that it counteracts the excessive secretion of cytokines. There are even more studies that focus on long-term follow-up; thus, the potential for major side effects can be analyzed more clearly. Finally, the ethical use of stem cells from fetal or infant origin needs to be regulated. The study was registered in PROSPERO (no. CRD42021229038). The limitations of the study were because of the methodology employed, the sample was not very large, and the follow-up period of the clinical studies was relatively short.

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Role of Mesenchymal Stem Cell-Conditioned Medium (MSC-CM) in the Bone Regeneration: A Systematic Review from 2007-2018

Annual Research & Review in Biology ◽

10.9734/arrb/2019/v31i230045 ◽

2019 ◽

pp. 1-16

Author(s):

Ismail Hadisoebroto Dilogo ◽

Jessica Fiolin

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Bone Regeneration ◽

Conditioned Medium ◽

Bone Healing ◽

In Vitro Studies ◽

In Vivo Studies

Background: The therapeutic value of mesenchymal stem cells (MSCs) in tissue engineering and regenerative medicine is attributable in part to paracrine pathways triggered by several secreted factors secreted into culture media. The secreted factor here is known as the conditioned medium (CM) or secretome. Objectives: This review is aimed to investigate and summarise the in-vitro, pre-clinical in-vivo studies regarding the role of CM-MSC in bone regeneration from 2007 until 2018 Data Sources: A systematic literature search on PubMed, MEDLINE, OVID, Scopus and Cochrane library was carried out by using search terms: Secretome, conditioned medium, mesenchymal stem cell, bone healing, osteogenic, osteogenesis. Methods: A total of 611 articles were reviewed. Ten articles were identified as relevant for this systematic literature review. Results: Three tables of studies were constructed for in vitro studies and in-vivo studies. Conclusion: All of the included in-vitro studies and in-vivo studies have shown a promoting effect of bone regeneration at various stages. Although there are no clinical studies regarding the use of CM-MSC in the human bone regeneration that have been conducted, transplantation of secretome has shown a promising result in the acceleration of bone healing process.

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Stem cell-based therapy for COVID-19 and ARDS: a systematic review

npj Regenerative Medicine ◽

10.1038/s41536-021-00181-9 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Gabriele Zanirati ◽

Laura Provenzi ◽

Lucas Lobraico Libermann ◽

Sabrina Comin Bizotto ◽

Isadora Machado Ghilardi ◽

...

Keyword(s):

Systematic Review ◽

Stem Cells ◽

Clinical Trials ◽

Stem Cell ◽

Cell Therapy ◽

Clinical Studies ◽

Case Series ◽

Potential Candidate ◽

Phase I Clinical Trials ◽

Cell Based Therapy

AbstractDespite global efforts to establish effective interventions for coronavirus disease 2019 (COVID-19) and its major complications, such as acute respiratory distress syndrome (ARDS), the treatment remains mainly supportive. Hence, identifying an effective and safe therapy for severe COVID-19 is critical for saving lives. A significant number of cell-based therapies have been through clinical investigation. In this study, we performed a systematic review of clinical studies investigating different types of stem cells as treatments for COVID-19 and ARDS to evaluate the safety and potential efficacy of cell therapy. The literature search was performed using PubMed, Embase, and Scopus. Among the 29 studies, there were eight case reports, five Phase I clinical trials, four pilot studies, two Phase II clinical trials, one cohort, and one case series. Among the clinical studies, 21 studies used cell therapy to treat COVID-19, while eight studies investigated cell therapy as a treatment for ARDS. Most of these (75%) used mesenchymal stem cells (MSCs) to treat COVID-19 and ARDS. Findings from the analyzed articles indicate a positive impact of stem cell therapy on crucial immunological and inflammatory processes that lead to lung injury in COVID-19 and ARDS patients. Additionally, among the studies, there were no reported deaths causally linked to cell therapy. In addition to standard care treatments concerning COVID-19 management, there has been supportive evidence towards adjuvant therapies to reduce mortality rates and improve recovery of care treatment. Therefore, MSCs treatment could be considered a potential candidate for adjuvant therapy in moderate-to-severe COVID-19 cases and compassionate use.

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Role of Mesenchymal Stem Cell-Conditioned Medium (MSC-CM) in ligament or tendon healing: A Systematic Review from 1998-2018

Orthopaedic Journal of Sports Medicine ◽

10.1177/2325967120s00109 ◽

2020 ◽

Vol 8 (5_suppl5) ◽

pp. 2325967120S0010

Author(s):

Sholahuddin Rhatomy ◽

Tito Sumarwoto ◽

Andhi Prijosedjati ◽

Romaniyanto ◽

Thomas Edison Prasetyo

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Conditioned Medium ◽

Tendon Healing ◽

In Vitro Studies ◽

In Vivo Studies ◽

Cochrane Library

Background: The therapeutic value of mesenchymal stem cells (MSCs) in tissue engineering and regenerative medicine is attributable in part to paracrine pathways triggered by several secreted factors secreted into culture media. The secreted factor here is known as the conditioned medium (CM) or secretome. Objectives: This review is aimed to investigate and summarise the in-vitro, pre-clinical in-vivo studies regarding the role of CM-MSC in ligament or tendon healing from 1998 until 2018. Data Sources: A systematic literature search on PubMed, MEDLINE, OVID, Scopus, Google scholar, and Cochrane library was carried out by using search terms: Secretome, conditioned medium, mesenchymal stem cell, ligament, tendon and healing. Methods: A total of 904 articles were reviewed. Five articles were identified as relevant for this systematic literature review. Results: One tables of studies were constructed for in vitro studies and in-vivo studies. Conclusion: All of the included in-vitro studies and in-vivo studies have shown a promoting effect of ligament or tendon healing at various stages in vitro or in vivo. Although there are no clinical studies regarding the use of CM- MSC in the human ligament or tendon healing that have been conducted, transplantation of secretome has shown a promising result in the acceleration of ligament or tendon healing process.

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Focus on the therapeutic efficacy of 3BNC117 against HIV-1: In vitro studies, in vivo studies, clinical trials and challenges

International Immunopharmacology ◽

10.1016/j.intimp.2017.08.016 ◽

2017 ◽

Vol 52 ◽

pp. 44-50 ◽

Cited By ~ 3

Author(s):

Zhi-Jun Liu ◽

Jing Bai ◽

Feng-Li Liu ◽

Xiang-Yang Zhang ◽

Jing-Zhang Wang

Keyword(s):

Clinical Trials ◽

Therapeutic Efficacy ◽

In Vitro Studies ◽

In Vivo Studies ◽

Hiv 1

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Expanded mesenchymal stem cell transplantation is safe in both local injection and vein transfusion

Progress in Stem Cell ◽

10.15419/psc.v4i3-4.398 ◽

2017 ◽

Vol 4 (3-4) ◽

pp. 234-235 ◽

Cited By ~ 1

Author(s):

Vlassov V Salval ◽

Yone Moto

Keyword(s):

Stem Cells ◽

Clinical Trials ◽

Stem Cell ◽

Clinical Applications ◽

Local Injection ◽

Mesenchymal Stem Cell Transplantation ◽

Routine Treatment ◽

Drug Products ◽

The World

More than 500 clinical trials are using mesenchymal stem cells (MSCs) in the world to treat some different diseases. The safety of expanded MSC transplantation is the most important thing to ensure that this therapy can become the routine treatment for human diseases. More than five MSCs based stem cell drug products are approved at various countries demonstrated that expanded MSCs are safe in both local injection and transfusion. Moreover, some recent reports for 5 and 10 years followed-up clinical trials using expanded MSCs confirmed that there is not different tumorigenesis between the patients with and without expanded MSC transplantation. This letter aims to provide some evidences about the safety of expanded MSCs in clinical applications. However, the MSC quality should be stritcly controlled during the in vitro MSC expansion.

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Research Status of Mesenchymal Stem Cells in Liver Transplantation

Cell Transplantation ◽

10.1177/0963689719874786 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1490-1506 ◽

Cited By ~ 2

Author(s):

Yu You ◽

Di-guang Wen ◽

Jian-ping Gong ◽

Zuo-jin Liu

Keyword(s):

Stem Cells ◽

Liver Transplantation ◽

Clinical Trials ◽

Mesenchymal Stem Cells ◽

In Vivo Studies ◽

Cell Contact ◽

Clinical Effects ◽

Clinical Safety

Liver transplantation has been deemed the best choice for end-stage liver disease patients but immune rejection after surgery is still a serious problem. Patients have to take immunosuppressive drugs for a long time after liver transplantation, and this often leads to many side effects. Mesenchymal stem cells (MSCs) gradually became of interest to researchers because of their powerful immunomodulatory effects. In the past, a large number of in vitro and in vivo studies have demonstrated the great potential of MSCs for participation in posttransplant immunomodulation. In addition, MSCs also have properties that may potentially benefit patients undergoing liver transplantation. This article aims to provide an overview of the current understanding of the immunomodulation achieved by the application of MSCs in liver transplantation, to discuss the problems that may be encountered when using MSCs in clinical practice, and to describe some of the underlying capabilities of MSCs in liver transplantation. Cell–cell contact, soluble molecules, and exosomes have been suggested to be critical approaches to MSCs’ immunoregulation in vitro; however, the exact mechanism, especially in vivo, is still unclear. In recent years, the clinical safety of MSCs has been proven by a series of clinical trials. The obstacles to the clinical application of MSCs are decreasing, but large sample clinical trials involving MSCs are still needed to further study their clinical effects.

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Remdesivir: Critical Clinical Appraisal for COVID 19 Treatment

Drug Research ◽

10.1055/a-1288-4078 ◽

2020 ◽

Author(s):

Saptarshi Chatterjee

Keyword(s):

Clinical Trials ◽

Clinical Research ◽

Clinical Studies ◽

Promising Result ◽

Drug Repurposing ◽

In Vitro Studies ◽

Therapeutic Molecules ◽

Regulatory Aspect ◽

Plausible Mechanism

AbstractRemdesivir is presently been considered as ‘molecule of hope’ to curb the menace of COVID19. Non-availability of any USFDA approved drug has led to several attempt of drug-repurposing and development of new therapeutic molecules. However, Remdesivir has been found to be effective against a broad range of virus including SARS, MERS and COVID 19 through in-vitro studies. Several clinical research attempt are presently being conducted showing promising result yet not conclusive. This review summarized all such clinical trials to critically appraise the usage of Remdesivir against COVID 19 along with the publications related to the results of the clinical studies. The present regulatory aspect i. e. Emergency Use Authorization (EYA) and information of molecule and plausible mechanism is also dealt.

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Macrophage Induced Effect of Particulate Silica on Rat Mesenchymal Stem Cells In Vitro

Key Engineering Materials ◽

10.4028/www.scientific.net/kem.396-398.123 ◽

2008 ◽

Vol 396-398 ◽

pp. 123-126

Author(s):

Timothy Wilson ◽

Reeta Viitala ◽

Mervi Puska ◽

Mika Jokinen ◽

Risto Penttinen

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Cultures ◽

Culture Medium ◽

Matrix Protein ◽

Bioactive Glasses ◽

Significant Difference ◽

Silica Microparticles

The role of silica and macrophages in fibrosis is well documented, but in bone formation it is relatively unknown despite decades of research with bioactive glasses. In this study macrophages were isolated from rat peritoneal and then cultured for five days in the presence of two types of silica microparticles with different solubilities. After the fifth day the culture medium was collected, purified and used as an additive in bone marrow derived rat stem cell cultures. The stem cells were cultured for five days in α-mem containing only 0,5% of FCS, enabling cell survival but disrupting their proliferation. As controls, stem cells were also cultured in α-mem containing silica microparticles. At days one and five the amount of soluble collagen was assayed from the culture medium and the cells were counted. All stem cell cultures with macrophage medium additives were found to be proliferative, with statistically significant difference to controls. However, collagen was only produced in cultures containing medium from macrophages cultured with fast-dissolving silica microparticles. This suggests that silica can induce cell proliferation and extra cellular matrix protein secretion which is mediated by macrophages, and that the solubility of silica is also a major factor in this reaction.

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Differential Role for VLA-5 in Mobilization of Heamotopoieic Stem Cells Toward Peripheral Blood and Homing to Bone Marrow and Spleen.

Blood ◽

10.1182/blood.v106.11.2190.2190 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2190-2190 ◽

Cited By ~ 1

Author(s):

Pieter K. Wierenga ◽

Ellen Weersing ◽

Bert Dontje ◽

Gerald de Haan ◽

Ronald P. van Os

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Progenitor Cells ◽

Peripheral Blood ◽

Hematopoietic Stem ◽

Late Antigen ◽

Cell Mobilization

Abstract Adhesion molecules have been implicated in the interactions of hematopoietic stem and progenitor cells with the bone marrow extracellular matrix and stromal cells. In this study we examined the role of very late antigen-5 (VLA-5) in the process of stem cell mobilization and homing after stem cell transplantation. In normal bone marrow (BM) from CBA/H mice 79±3 % of the cells in the lineage negative fraction express VLA-5. After mobilization with cyclophosphamide/G-CSF, the number of VLA-5 expressing cells in mobilized peripheral blood cells (MPB) decreases to 36±4%. The lineage negative fraction of MPB cells migrating in vitro towards SDF-1α (M-MPB) demonstrated a further decrease to 3±1% of VLA-5 expressing cells. These data are suggestive for a downregulation of VLA-5 on hematopoietic cells during mobilization. Next, MPB cells were labelled with PKH67-GL and transplanted in lethally irradiated recipients. Three hours after transplantation an increase in VLA-5 expressing cells was observed which remained stable until 24 hours post-transplant. When MPB cells were used the percentage PKH-67GL+ Lin− VLA-5+ cells increased from 36% to 88±4%. In the case of M-MPB cells the number increased from 3% to 33±5%. Although the increase might implicate an upregulation of VLA-5, we could not exclude selective homing of VLA-5+ cells as a possible explanation. Moreover, we determined the percentage of VLA-5 expressing cells immediately after transplantation in the peripheral blood of the recipients and were not able to observe any increase in VLA-5+ cells in the first three hours post-tranpslant. Finally, we separated the MPB cells in VLA-5+ and VLA-5− cells and plated these cells out in clonogenic assays for progenitor (CFU-GM) and stem cells (CAFC-day35). It could be demonstared that 98.8±0.5% of the progenitor cells and 99.4±0.7% of the stem cells were present in the VLA-5+ fraction. Hence, VLA-5 is not downregulated during the process of mobilization and the observed increase in VLA-5 expressing cells after transplantation is indeed caused by selective homing of VLA-5+ cells. To shed more light on the role of VLA-5 in the process of homing, BM and MPB cells were treated with an antibody to VLA-5. After VLA-5 blocking of MPB cells an inhibition of 59±7% in the homing of progenitor cells in bone marrow could be found, whereas homing of these subsets in the spleen of the recipients was only inhibited by 11±4%. For BM cells an inhibition of 60±12% in the bone marrow was observed. Homing of BM cells in the spleen was not affected at all after VLA-5 blocking. Based on these data we conclude that mobilization of hematopoietic progenitor/stem cells does not coincide with a downregulation of VLA-5. The observed increase in VLA-5 expressing cells after transplantation is caused by preferential homing of VLA-5+ cells. Homing of progenitor/stem cells to the bone marrow after transplantation apparantly requires adhesion interactions that can be inhibited by blocking VLA-5 expression. Homing to the spleen seems to be independent of VLA-5 expression. These data are indicative for different adhesive pathways in the process of homing to bone marrow or spleen.

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The Role of Nucleophosmin In Hematopoietic Stem Cells and the Pathogenesis of Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v116.21.95.95 ◽

2010 ◽

Vol 116 (21) ◽

pp. 95-95 ◽

Cited By ~ 1

Author(s):

Keisuke Ito ◽

Paolo Sportoletti ◽

John G Clohessy ◽

Grisendi Silvia ◽

Pier Paolo Pandolfi

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Myelodysplastic Syndrome ◽

Cell Biology ◽

De Novo ◽

Stem Cell Biology ◽

Hematopoietic Stem

Abstract Abstract 95 Myelodysplastic syndrome (MDS) is an incurable stem cell disorder characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Nucleophosmin (NPM) is directly implicated in primitive hematopoiesis, the pathogenesis of hematopoietic malignancies and more recently of MDS. However, little is known regarding the molecular role and function of NPM in MDS pathogenesis and in stem cell biology. Here we present data demonstrating that NPM plays a critical role in the maintenance of hematopoietic stem cells (HSCs) and the transformation of MDS into leukemia. NPM is located on chromosome 5q and is frequently lost in therapy-related and de novo MDS. We have previously shown that Npm1 acts as a haploinsufficient tumor suppressor in the hematopoietic compartment and Npm1+/− mice develop a hematologic syndrome with features of human MDS, including increased susceptibility to leukemogenesis. As HSCs have been demonstrated to be the target of the primary neoplastic event in MDS, a functional analysis of the HSC compartment is essential to understand the molecular mechanisms in MDS pathogenesis. However, the role of NPM in adult hematopoiesis remains largely unknown as Npm1-deficiency leads to embryonic lethality. To investigate NPM function in adult hematopoiesis, we have generated conditional knockout mice of Npm1, using the Cre-loxP system. Analysis of Npm1 conditional mutants crossed with Mx1-Cre transgenic mice reveals that Npm1 plays a crucial role in adult hematopoiesis and ablation of Npm1 in adult HSCs leads to aberrant cycling and followed by apoptosis. Analysis of cell cycle status revealed that HSCs are impaired in their ability to maintain quiescence after Npm1-deletion and are rapidly depleted in vivo as well as in vitro. Competitive reconstitution assay revealed that Npm1 acts cell-autonomously to maintain HSCs. Conditional inactivation of Npm1 leads to an MDS phenotype including a profoundly impaired ability to differentiate into cells of the erythroid lineage, megakaryocyte dyspoiesis and centrosome amplification. Furthermore, Npm1 loss evokes a p53-dependent response and Npm1-deleted HSCs undergo apoptosis in vivo and in vitro. Strikingly, transfer of the Npm1 mutation into a p53-null background rescued the apoptosis of Npm1-ablated HSCs and resulted in accelerated transformation to an aggressive and lethal form of acute myeloid leukemia. Our findings highlight the crucial role of NPM in stem cell biology and identify a new mechanism by which MDS can progress to leukemia. This has important therapeutic implications for de novo MDS as well as therapy-related MDS, which is known to rapidly evolve to leukemia with frequent loss or mutation of TRP53. Disclosures: No relevant conflicts of interest to declare.

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