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Stem and Progenitor Cells: Self-Renewal, Commitment and Differentiation – Conceptual and Practical Aspects

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (15 January 2022) | Viewed by 19205

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Special Issue Editor

Dr. Zoran Ivanovic

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Guest Editor

1. Etablissement Français du Sang Nouvelle Aquitaine, Place Amélie Raba Léon, CS22010, CEDEX, 33075 Bordeaux, France
2. Inserm Bordeaux UMR 1035, 33000 Bordeaux, France
3. Department of Biological and Medical Sciences, Campus Carreire, University of Bordeaux, 33000 Bordeaux, France
Interests: somatic stem cells; self-renewal; metabolic profile and stemness; anaerobiosis and stemness; ex vivo cell engineering
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Special Issue Information

Dear Colleagues,

A Special Issue on “Stem and Progenitor Cells: Self-Renewal, Commitment and Differentiation – Conceptual and Practical Aspects” is being prepared for the journal Biomolecules. The fate of somatic stem cells is determined by a decision to proliferate without commitment or to commit and differentiate. Since both “symmetric” and “asymmetric” divisions are an option, the life span of a clone depends on the proliferative capacity of its initial stem cell and the extrinsic factors. This proliferative capacity of the initial stem cell, in fact, limits the total number of cells produced during the life span of a clone. The total number of cells produced during the proliferative history of a clone is in reality determined by the ratio between self-renewing and commitment/differentiation divisions. To harness stem cells and enable an appropriate ex vivo production of immature and mature cells, depending on the clinical demand, it is necessary to reveal the mechanisms of self-renewal, commitment, and differentiation. Original manuscript and reviews dealing with any aspect (physiology, biochemistry, cell biology, molecular biology, etc.) of somatic stem and progenitor cell self-renewal, commitment, and differentiation are welcome, as well as translational studies related to this issue.

Dr. Zoran Ivanovic
Guest Editor

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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

somatic stem cells
progenitor cells
self-renewal
commitment
cell engineering
regenerative medicine
cell therapy
ex vivo
mechanisms
translation

Published Papers (7 papers)

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Research

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21 pages, 1977 KiB

Open AccessArticle

The Influence of Heterochronic Non-Myeloablative Bone Marrow Transplantation on the Immune System, Frailty, General Health, and Longevity of Aged Murine Recipients

by Katerina Jazbec, Mojca Jež, Urban Švajger, Boštjan Smrekar, Simona Miceska, Uroš Rajčevič, Mojca Justin, Janja Završnik, Tadej Malovrh, Tanja Švara, Mitja Gombač, Živa Ramšak and Primož Rožman

Biomolecules 2022, 12(4), 595; https://doi.org/10.3390/biom12040595 - 18 Apr 2022

Cited by 2 | Viewed by 2553

Abstract

The stem cell theory of aging postulates that stem cells become inefficient at maintaining the original functions of the tissues. We, therefore, hypothesized that transplanting young bone marrow (BM) to old recipients would lead to rejuvenating effects on immunity, followed by improved general health, decreased frailty, and possibly life span extension. We developed a murine model of non-myeloablative heterochronic BM transplantation in which old female BALB/c mice at 14, 16, and 18(19) months of age received altogether 125.1 ± 15.6 million nucleated BM cells from young male donors aged 7–13 weeks. At 21 months, donor chimerism was determined, and the immune system’s innate and adaptive arms were analyzed. Mice were then observed for general health and frailty until spontaneous death, when their lifespan, post-mortem examinations, and histopathological changes were recorded. The results showed that the old mice developed on average 18.7 ± 9.6% donor chimerism in the BM and showed certain improvements in their innate and adaptive arms of the immune system, such as favorable counts of neutrophils in the spleen and BM, central memory Th cells, effector/effector memory Th and Tc cells in the spleen, and B1a and B1b cells in the peritoneal cavity. Borderline enhanced lymphocyte proliferation capacity was also seen. The frailty parameters, pathomorphological results, and life spans did not differ significantly in the transplanted vs. control group of mice. In conclusion, although several favorable effects are obtained in our heterochronic non-myeloablative transplantation model, additional optimization is needed for better rejuvenation effects. Full article

(This article belongs to the Special Issue Stem and Progenitor Cells: Self-Renewal, Commitment and Differentiation – Conceptual and Practical Aspects)

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16 pages, 2943 KiB

Open AccessArticle

Regulatory Crosstalk between Physiological Low O₂ Concentration and Notch Pathway in Early Erythropoiesis

by Véronique Labat, Eva Nguyen van Thanh dit Bayard, Alice Refeyton, Mathilde Huart, Maryse Avalon, Christelle Debeissat, Laura Rodriguez, Philippe Brunet de la Grange, Zoran Ivanovic and Marija Vlaski-Lafarge

Biomolecules 2022, 12(4), 540; https://doi.org/10.3390/biom12040540 - 2 Apr 2022

Viewed by 2010

Abstract

Physiological low oxygen (O₂) concentration (<5%) favors erythroid development ex vivo. It is known that low O₂ concentration, via the stabilization of hypoxia-induced transcription factors (HIFs), intervenes with Notch signaling in the control of cell fate. In addition, Notch activation is implicated in the regulation of erythroid differentiation. We test here if the favorable effects of a physiological O₂ concentration (3%) on the amplification of erythroid progenitors implies a cooperation between HIFs and the Notch pathway. To this end, we utilized a model of early erythropoiesis ex vivo generated from cord blood CD34⁺ cells transduced with shHIF1α and shHIF2α at 3% O₂ and 20% O₂ in the presence or absence of the Notch pathway inhibitor. We observed that Notch signalization was activated by Notch2R–Jagged1 ligand interaction among progenitors. The inhibition of the Notch pathway provoked a modest reduction in erythroid cell expansion and promoted erythroid differentiation. ShHIF1α and particularly shHIF2α strongly impaired erythroid progenitors’ amplification and differentiation. Additionally, HIF/NOTCH signaling intersects at the level of multipotent progenitor erythroid commitment and amplification of BFU-E. In that, both HIFs contribute to the expression of Notch2R and Notch target gene HES1. Our study shows that HIF, particularly HIF2, has a determining role in the early erythroid development program, which includes Notch signaling. Full article

(This article belongs to the Special Issue Stem and Progenitor Cells: Self-Renewal, Commitment and Differentiation – Conceptual and Practical Aspects)

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14 pages, 2801 KiB

Open AccessArticle

Alpha Lipoic-Acid Potentiates Ex Vivo Expansion of Human Steady-State Peripheral Blood Hematopoietic Primitive Cells

by Christelle Debeissat, Maryse Avalon, Mathilde Huart, Pascale Duchez, Laura Rodriguez, Marija Vlaski-Lafarge, Zoran Ivanovic and Philippe Brunet de la Grange

Biomolecules 2022, 12(3), 431; https://doi.org/10.3390/biom12030431 - 11 Mar 2022

Viewed by 2082

Abstract

Steady state peripheral blood (SSPB) contains hematopoietic stem and progenitor cells (HSPCs) presenting characteristics of real hematopoietic stem cells, and thus represents an interesting alternative cell supply for hematopoietic cell transplantation. Development of ex vivo expansion strategies could overcome the low HSPC numbers usually rescued from SSPB. We investigated the effect of alpha lipoic acid (ALA) on ex vivo culture of SSPB CD34 positive (CD34^pos) cells on primitive cell expansion, cell cycle, and oxidative metabolism as estimated by determining the ROS and GSH content. ALA increased the ex vivo expansion of total CD34^pos cells and of phenotypically defined CD34^pos HSPCs subpopulations that retained in vivo repopulating capacity, concomitantly to a decreased expansion of differentiating cells. ALA did not modify cell cycle progression nor the proliferation of ex vivo expanded CD34^pos cells, and coherently did not affect the ROS level. On the contrary, ALA decreased the proliferation and disturbed cell cycle progression of cells reaching a differentiated status, a phenomenon that seems to be associated with a drop in ROS level. Nonetheless, ALA affected the redox status of hematopoietic primitive cells, as it reproducibly increased GSH content. In conclusion, ALA represents an interesting molecule for the improvement of ex vivo expansion strategies and further clinical application in hematopoietic cell transplantation (HCT). Full article

(This article belongs to the Special Issue Stem and Progenitor Cells: Self-Renewal, Commitment and Differentiation – Conceptual and Practical Aspects)

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23 pages, 4236 KiB

Open AccessArticle

Vitamin D3 Stimulates Proliferation Capacity, Expression of Pluripotency Markers, and Osteogenesis of Human Bone Marrow Mesenchymal Stromal/Stem Cells, Partly through SIRT1 Signaling

by Ana Borojević, Aleksandra Jauković, Tamara Kukolj, Slavko Mojsilović, Hristina Obradović, Drenka Trivanović, Milena Živanović, Željko Zečević, Marija Simić, Borko Gobeljić, Dragana Vujić and Diana Bugarski

Biomolecules 2022, 12(2), 323; https://doi.org/10.3390/biom12020323 - 18 Feb 2022

Cited by 17 | Viewed by 2870

Abstract

The biology of vitamin D3 is well defined, as are the effects of its active metabolites on various cells, including mesenchymal stromal/stem cells (MSCs). However, the biological potential of its precursor, cholecalciferol (VD3), has not been sufficiently investigated, although its significance in regenerative medicine—mainly in combination with various biomaterial matrices—has been recognized. Given that VD3 preconditioning might also contribute to the improvement of cellular regenerative potential, the aim of this study was to investigate its effects on bone marrow (BM) MSC functions and the signaling pathways involved. For that purpose, the influence of VD3 on BM-MSCs obtained from young human donors was determined via MTT test, flow cytometric analysis, immunocytochemistry, and qRT-PCR. Our results revealed that VD3, following a 5-day treatment, stimulated proliferation, expression of pluripotency markers (NANOG, SOX2, and Oct4), and osteogenic differentiation potential in BM-MSCs, while it reduced their senescence. Moreover, increased sirtuin 1 (SIRT1) expression was detected upon treatment with VD3, which mediated VD3-promoted osteogenesis and, partially, the stemness features through NANOG and SOX2 upregulation. In contrast, the effects of VD3 on proliferation, Oct4 expression, and senescence were SIRT1-independent. Altogether, these data indicate that VD3 has strong potential to modulate BM-MSCs’ features, partially through SIRT1 signaling, although the precise mechanisms merit further investigation. Full article

(This article belongs to the Special Issue Stem and Progenitor Cells: Self-Renewal, Commitment and Differentiation – Conceptual and Practical Aspects)

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15 pages, 3311 KiB

Open AccessArticle

Inflammation Promotes Oxidative and Nitrosative Stress in Chronic Myelogenous Leukemia

by Dragoslava Đikić, Andrija Bogdanović, Dragana Marković, Olivera Mitrović-Ajtić, Tijana Subotički, Miloš Diklić, Milica Vukotić, Teodora Dragojević, Emilija Živković, Juan F. Santibanez and Vladan P. Čokić

Biomolecules 2022, 12(2), 247; https://doi.org/10.3390/biom12020247 - 3 Feb 2022

Cited by 2 | Viewed by 2138

Abstract

Chronic inflammation is characterized by the production of reactive oxygen species (ROS), reactive nitrogen species, and inflammatory cytokines in myeloproliferative neoplasms (MPNs). In addition to these parameters, the aim of this study was to analyze the influence of ROS on the proliferation-related AKT/mTOR signaling pathway and the relationship with inflammatory factors in chronic myelogenous leukemia (CML). The activity of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase is reduced in erythrocytes while levels of the oxidative stress markers malondialdehyde and protein carbonyl are elevated in the plasma of patients with CML. In addition, nitrogen species (nitrotyrosine, iNOS, eNOS) and inflammation markers (IL-6, NFkB, and S100 protein) were increased in granulocytes of CML while anti-inflammatory levels of IL-10 were decreased in plasma. CML granulocytes exhibited greater resistance to cytotoxic H₂O₂ activity compared to healthy subjects. Moreover, phosphorylation of the apoptotic p53 protein was reduced while the activity of the AKT/mTOR signaling pathway was increased, which was further enhanced by oxidative stress (H₂O₂) in granulocytes and erythroleukemic K562 cells. IL-6 caused oxidative stress and DNA damage that was mitigated using antioxidant or inhibition of inflammatory NFkB transcription factor in K562 cells. We demonstrated the presence of oxidative and nitrosative stress in CML, with the former mediated by AKT/mTOR signaling and stimulated by inflammation. Full article

(This article belongs to the Special Issue Stem and Progenitor Cells: Self-Renewal, Commitment and Differentiation – Conceptual and Practical Aspects)

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12 pages, 1657 KiB

Open AccessArticle

Nitric Oxide Mediation in Hydroxyurea and Nitric Oxide Metabolites’ Inhibition of Erythroid Progenitor Growth

by Tijana Subotički, Olivera Mitrović Ajtić, Dragoslava Djikić, Marijana Kovačić, Juan F. Santibanez, Milica Tošić and Vladan P. Čokić

Biomolecules 2021, 11(11), 1562; https://doi.org/10.3390/biom11111562 - 21 Oct 2021

Cited by 2 | Viewed by 1459

Abstract

In several systems, hydroxyurea has been shown to trigger nitric oxide (NO) release or activation of NO synthase (NOS). To elucidate this duality in its pharmacological effects, during myelosuppression, we individually examined hydroxyurea’s (NO releasing agent) and NO metabolites’ (stable NO degradation products) effects on erythroid colony growth and NOS/NO levels in mice using NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO). Hydroxyurea and nitrite/nitrate decreased the bone marrow cellularity that was blocked by PTIO only for the NO metabolites. Hydroxyurea inhibition of colony-forming unit-erythroid (CFU-E) formation and reticulocytes was reversed by PTIO. Moreover, hydroxyurea, through a negative feedback mechanism, reduced inducible NOS (iNOS) expressing cells in CFU-E, also prevented by PTIO. Nitrate inhibition of burst-forming units-erythroid (BFU-E) colony growth was blocked by PTIO, but not in mature CFU-E. The presented results reveal that NO release and/or production mediates the hydroxyurea inhibition of mature erythroid colony growth and the frequency of iNOS immunoreactive CFU-E. Full article

(This article belongs to the Special Issue Stem and Progenitor Cells: Self-Renewal, Commitment and Differentiation – Conceptual and Practical Aspects)

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Review

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39 pages, 12353 KiB

Open AccessReview

Using Vertebrate Stem and Progenitor Cells for Cellular Agriculture, State-of-the-Art, Challenges, and Future Perspectives

by Teodora Knežić, Ljiljana Janjušević, Mila Djisalov, Supansa Yodmuang and Ivana Gadjanski

Biomolecules 2022, 12(5), 699; https://doi.org/10.3390/biom12050699 - 13 May 2022

Cited by 8 | Viewed by 5035

Abstract

Global food systems are under significant pressure to provide enough food, particularly protein-rich foods whose demand is on the rise in times of crisis and inflation, as presently existing due to post-COVID-19 pandemic effects and ongoing conflict in Ukraine and resulting in looming food insecurity, according to FAO. Cultivated meat (CM) and cultivated seafood (CS) are protein-rich alternatives for traditional meat and fish that are obtained via cellular agriculture (CA) i.e., tissue engineering for food applications. Stem and progenitor cells are the building blocks and starting point for any CA bioprocess. This review presents CA-relevant vertebrate cell types and procedures needed for their myogenic and adipogenic differentiation since muscle and fat tissue are the primary target tissues for CM/CS production. The review also describes existing challenges, such as a need for immortalized cell lines, or physical and biochemical parameters needed for enhanced meat/fat culture efficiency and ways to address them. Full article

(This article belongs to the Special Issue Stem and Progenitor Cells: Self-Renewal, Commitment and Differentiation – Conceptual and Practical Aspects)

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