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Stem Cells and Regenerative Medicine: In Vitro and In Vivo Studies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 31 July 2024 | Viewed by 11024

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Special Issue Editor

Dr. Alessia Peserico

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Guest Editor

Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy
Interests: stem cell homing; nanoparticle assisted stem cell tracking; regenerative medicine ovarian follicologenesis in mammals

Special Issue Information

Dear Colleagues,

In recent years, stem cell therapy has become a very promising and advanced scientific research topic. Stem cells have the capability to self-renew and to differentiate into several cell types, and are involved in physiological regeneration processes.

In the context of tissue injury, stem cells have gained worldwide attention because of their immense potential for immunomodulation and their therapeutic function. Stem cells can migrate to tissue injury areas to contribute to immune modulation, secrete anti-inflammatory cytokines, and hide themselves from the immune system.

With so many stem cell replacement therapies currently going through clinical trials, there is a compelling need to understand the mechanisms behind a successful therapy, and one of the critical points of their discovery is to monitor and manage stem cell migration, proliferation, differentiation, and organization in vitro as well as in vivo. In this context, the use of biomaterials to manipulate stem cells providing control of their behavior and homing has received great interest, becoming a pivotal step for the development of innovative stem cell transplantation solutions.

This Special Issue aims to provide the latest updates on stem cells and their in vitro and in vivo applications in the regenerative medicine field, opening novel and advanced strategies for tissue-repairing processes and many other clinical applications.

Original articles, up-to-date review articles, and commentaries addressing this topic are all welcome.

Dr. Alessia Peserico
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

stem cells
stem cell homing
stem cell tracking
regeneration
tissue injury
immunomodulation
biomaterials
tissue-on-a-chip
organoids
differentiation

Published Papers (7 papers)

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Research

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23 pages, 21082 KiB

Open AccessArticle

The Effects of Fucoidan Derived from Sargassum filipendula and Fucus vesiculosus on the Survival and Mineralisation of Osteogenic Progenitors

by Dhanak Gupta, Diana C. Martinez, Miguel Angel Puertas-Mejía, Vanessa L. Hearnden and Gwendolen C. Reilly

Int. J. Mol. Sci. 2024, 25(4), 2085; https://doi.org/10.3390/ijms25042085 - 8 Feb 2024

Viewed by 916

Abstract

Osteosarcoma is a bone cancer primarily affecting teenagers. It has a poor prognosis and diminished quality of life after treatment due to chemotherapy side effects, surgical complications and post-surgical osteoporosis risks. The sulphated polysaccharide fucoidan, derived from brown algae, has been a subject of interest for its potential anti-cancer properties and its impact on bone regeneration. This study explores the influence of crude, low-molecular-weight (LMW, 10–50 kDa), medium-molecular-weight (MMW, 50–100 kDa) and high-molecular-weight (HMW, >100 kDa) fractions from Sargassum filipendula, harvested from the Colombian sea coast, as well as crude fucoidan from Fucus vesiculosus, on a specific human osteoprogenitor cell type, human embryonic-derived mesenchymal stem cells. Fourier transform infrared spectroscopy coupled with attenuated total reflection (FTIR-ATR) results showed the highest sulphation levels and lowest uronic acid content in crude extract from F. vesiculosus. There was a dose-dependent drop in focal adhesion formation, proliferation and osteogenic differentiation of cells for all fucoidan types, but the least toxicity was observed for LMW and MMW. Transmission electron microscopy (TEM), JC-1 (5,50,6,60-tetrachloro-1,10,3,30-tetraethylbenzimi-dazolylcarbocyanine iodide) staining and cytochrome c analyses confirmed mitochondrial damage, swollen ER and upregulated autophagy due to fucoidans, with the highest severity in the case of F. vesiculosus fucoidan. Stress-induced apoptosis-like cell death by F. vesiculosus fucoidan and stress-induced necrosis-like cell death by S. filipendula fucoidans were also confirmed. LMW and MMW doses of <200 ng/mL were the least toxic and showed potential osteoinductivity. This research underscores the multifaceted impact of fucoidans on osteoprogenitor cells and highlights the delicate balance between potential therapeutic benefits and the challenges involved in using fucoidans for post-surgery treatments in patients with osteosarcoma. Full article

(This article belongs to the Special Issue Stem Cells and Regenerative Medicine: In Vitro and In Vivo Studies)

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20 pages, 9464 KiB

Open AccessArticle

Immortalized Canine Adipose-Derived Mesenchymal Stem Cells Maintain the Immunomodulatory Capacity of the Original Primary Cells

by Yuyo Yasumura, Takahiro Teshima, Tomokazu Nagashima, Masaki Michishita, Takashi Takano, Yoshiaki Taira, Ryohei Suzuki and Hirotaka Matsumoto

Int. J. Mol. Sci. 2023, 24(24), 17484; https://doi.org/10.3390/ijms242417484 - 14 Dec 2023

Cited by 1 | Viewed by 913

Abstract

Mesenchymal stem cells (MSCs) are a promising cell source for stem cell therapy of intractable diseases in veterinary medicine, but donor-dependent cellular heterogeneity is an issue that influences therapeutic efficacy. Thus, we previously established immortalized cells that maintain the fundamental properties of primary cells, but functional evaluation had not been performed. Therefore, we evaluated the immunomodulatory capacity of the immortalized canine adipose-derived MSCs (cADSCs) in vitro and in vivo to investigate whether they maintain primary cell functions. C57BL/6J mice were treated with dextran sulfate sodium (DSS) to induce colitis, injected intraperitoneally with immortalized or primary cADSCs on day 2 of DSS treatment, and observed for 10 days. Administration of immortalized cADSCs improved body weight loss and the disease activity index (DAI) in DSS-induced colitic mice by shifting peritoneal macrophage polarity from the M1 to M2 phenotype, suppressing T helper (Th) 1/Th17 cell responses and inducing regulatory T (Treg) cells. They also inhibited the proliferation of mouse and canine T cells in vitro. These immunomodulatory effects were comparable with primary cells. These results highlight the feasibility of our immortalized cADSCs as a cell source for stem cell therapy with stable therapeutic efficacy because they maintain the immunomodulatory capacity of primary cells. Full article

(This article belongs to the Special Issue Stem Cells and Regenerative Medicine: In Vitro and In Vivo Studies)

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21 pages, 4584 KiB

Open AccessArticle

Integrative Analysis Reveals the Diverse Effects of 3D Stiffness upon Stem Cell Fate

by Muxin Yue, Yunsong Liu, Ping Zhang, Zheng Li and Yongsheng Zhou

Int. J. Mol. Sci. 2023, 24(11), 9311; https://doi.org/10.3390/ijms24119311 - 26 May 2023

Cited by 5 | Viewed by 1491

Abstract

The origin of life and native tissue development are dependent on the heterogeneity of pluripotent stem cells. Bone marrow mesenchymal stem cells (BMMSCs) are located in a complicated niche with variable matrix stiffnesses, resulting in divergent stem cell fates. However, how stiffness drives stem cell fate remains unknown. For this study, we performed whole-gene transcriptomics and precise untargeted metabolomics sequencing to elucidate the complex interaction network of stem cell transcriptional and metabolic signals in extracellular matrices (ECMs) with different stiffnesses, and we propose a potential mechanism involved in stem cell fate decision. In a stiff (39~45 kPa) ECM, biosynthesis of aminoacyl-tRNA was up-regulated, and increased osteogenesis was also observed. In a soft (7~10 kPa) ECM, biosynthesis of unsaturated fatty acids and deposition of glycosaminoglycans were increased, accompanied by enhanced adipogenic/chondrogenic differentiation of BMMSCs. In addition, a panel of genes responding to the stiffness of the ECM were validated in vitro, mapping out the key signaling network that regulates stem cells’ fate decisions. This finding of “stiffness-dependent manipulation of stem cell fate” provides a novel molecular biological basis for development of potential therapeutic targets within tissue engineering, from both a cellular metabolic and a biomechanical perspective. Full article

(This article belongs to the Special Issue Stem Cells and Regenerative Medicine: In Vitro and In Vivo Studies)

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23 pages, 5568 KiB

Open AccessArticle

AEC and AFMSC Transplantation Preserves Fertility of Experimentally Induced Rat Varicocele by Expressing Differential Regenerative Mechanisms

by Alessia Peserico, Barbara Barboni, Valentina Russo, Delia Nardinocchi, Maura Turriani, Costanza Cimini, Nicola Bernabò, Ornella Parolini, Antonietta Rosa Silini, Ivana Antonucci, Liborio Stuppia, Paolo Berardinelli, Ilaria Falanga, Davide Perruzza, Luca Valbonetti and Annunziata Mauro

Int. J. Mol. Sci. 2023, 24(10), 8737; https://doi.org/10.3390/ijms24108737 - 14 May 2023

Viewed by 1633

Abstract

Amniotic membrane and amniotic fluid derived cells are regarded as a promising stem cell source for developing regenerative medicine techniques, although they have never been tested on male infertility diseases such as varicocele (VAR). The current study aimed to examine the effects of two distinct cell sources, human Amniotic Fluid Mesenchymal Stromal Cells (hAFMSCs) and amniotic epithelial cells (hAECs), on male fertility outcomes in a rat induced VAR model. To explain cell-dependent enhancement of reproductive outcomes in rats transplanted with hAECs and hAFMSCs, insights on testis morphology, endocannabinoid system (ECS) expression and inflammatory tissue response have been carried out alongside cell homing assessment. Both cell types survived 120 days post-transplantation by modulating the ECS main components, promoting proregenerative M2 macrophages (Mφ) recruitment and a favorable anti-inflammatory IL10 expression pattern. Of note, hAECs resulted to be more effective in restoring rat fertility rate by enhancing both structural and immunoresponse mechanisms. Moreover, immunofluorescence analysis revealed that hAECs contributed to CYP11A1 expression after transplantation, whereas hAFMSCs moved towards the expression of Sertoli cell marker, SOX9, confirming a different contribution into the mechanisms leading to testis homeostasis. These findings highlight, for the first time, a distinct role of amniotic membrane and amniotic fluid derived cells in male reproduction, thus proposing innovative targeted stem-based regenerative medicine protocols for remedying high-prevalence male infertility conditions such as VAR. Full article

(This article belongs to the Special Issue Stem Cells and Regenerative Medicine: In Vitro and In Vivo Studies)

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14 pages, 6025 KiB

Open AccessArticle

Impact of Canine Amniotic Mesenchymal Stem Cell Conditioned Media on the Wound Healing Process: In Vitro and In Vivo Study

by Filip Humenik, Marcela Maloveská, Nikola Hudáková, Patrícia Petroušková, Zuzana Šufliarska, Ľubica Horňáková, Alexandra Valenčáková, Martin Kožár, Barbora Šišková, Dagmar Mudroňová, Martin Bartkovský and Daša Čížková

Int. J. Mol. Sci. 2023, 24(9), 8214; https://doi.org/10.3390/ijms24098214 - 4 May 2023

Cited by 2 | Viewed by 1623

Abstract

The aim of this study was to provide a beneficial treatment effect of mesenchymal stem cell products derived from the canine amniotic membrane (AM-MSC) on the complicated wound healing process in dogs. AM-MSCs were characterized in terms of morphology, phenotypic profile, and multilineage differentiation potential. The in vitro study of the effect of canine amniotic mesenchymal stem cell conditioned media (AMMSC-CM) on a primary skin fibroblast cell culture scratch assay showed a decrease in the measured scratch area of about 66.39% against the negative control (Dulbecco’s Modified Eagle’s Medium—32.55%) and the positive control (Dulbecco’s Modified Eagle’s Medium supplemented with FGF2, N2, B27, and EGF—82.077%) after 72 h treatment. In the experimental study, seven dogs with complicated nonhealing wounds were treated with a combination of antibiotics, NSAIDs, and local AMMSC-CM application. After 15 days of therapy, we observed a 98.47% reduction in the wound surface area as opposed to 57.135% in the control group treated by conventional therapy based on debridement of necrotic tissue, antibiotic therapy, pain management, and change of wound dressing. Full article

(This article belongs to the Special Issue Stem Cells and Regenerative Medicine: In Vitro and In Vivo Studies)

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18 pages, 3657 KiB

Open AccessArticle

Impact of Adipose Tissue Depot Harvesting Site on the Multilineage Induction Capacity of Male Rat Adipose-Derived Mesenchymal Stem Cells: An In Vitro Study

by Hussein M. El-Husseiny, Masahiro Kaneda, Eman A. Mady, Tadashi Yoshida, Ahmed S. Doghish and Ryou Tanaka

Int. J. Mol. Sci. 2023, 24(8), 7513; https://doi.org/10.3390/ijms24087513 - 19 Apr 2023

Cited by 16 | Viewed by 2065

Abstract

Recently, substantial attention has been paid toward adipose-derived mesenchymal stem cells (AdMSCs) as a potential therapy in tissue engineering and regenerative medicine applications. Rat AdMSCs (r-AdMSCs) are frequently utilized. However, the influence of the adipose depot site on the multilineage differentiation potential of the r-AdMSCs is still ambiguous. Hence, the main objective of this study was to explore the influence of the adipose tissue harvesting location on the ability of r-AdMSCs to express the stem-cell-related markers and pluripotency genes, as well as their differentiation capacity, for the first time. Herein, we have isolated r-AdMSCs from the inguinal, epididymal, peri-renal, and back subcutaneous fats. Cells were compared in terms of their phenotype, immunophenotype, and expression of pluripotency genes using RT-PCR. Additionally, we investigated their potential for multilineage (adipogenic, osteogenic, and chondrogenic) induction using special stains confirmed by the expression of the related genes using RT-qPCR. All cells could positively express stem cell marker CD 90 and CD 105 with no significant in-between differences. However, they did not express the hematopoietic markers as CD 34 and CD 45. All cells could be induced successfully. However, epididymal and inguinal cells presented the highest capacity for adipogenic and osteogenic differentiation (21.36-fold and 11.63-fold for OPN, 29.69-fold and 26.68-fold for BMP2, and 37.67-fold and 22.35-fold for BSP, respectively, in epididymal and inguinal cells (p < 0.0001)). On the contrary, the subcutaneous cells exhibited a superior potential for chondrogenesis over the other sites (8.9-fold for CHM1 and 5.93-fold for ACAN, (p < 0.0001)). In conclusion, the adipose tissue harvesting site could influence the differentiation capacity of the isolated AdMSCs. To enhance the results of their employment in various regenerative cell-based therapies, it is thus vital to take the collection site selection into consideration. Full article

(This article belongs to the Special Issue Stem Cells and Regenerative Medicine: In Vitro and In Vivo Studies)

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Review

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17 pages, 903 KiB

Open AccessReview

Integration of iPSC-Derived Microglia into Brain Organoids for Neurological Research

by Muhammad Asif Mrza, Jitian He and Youwei Wang

Int. J. Mol. Sci. 2024, 25(6), 3148; https://doi.org/10.3390/ijms25063148 - 9 Mar 2024

Viewed by 1186

Abstract

The advent of Induced Pluripotent Stem Cells (iPSCs) has revolutionized neuroscience research. This groundbreaking innovation has facilitated the development of three-dimensional (3D) neural organoids, which closely mimicked the intricate structure and diverse functions of the human brain, providing an unprecedented platform for the in-depth study and understanding of neurological phenomena. However, these organoids lack key components of the neural microenvironment, particularly immune cells like microglia, thereby limiting their applicability in neuroinflammation research. Recent advancements focused on addressing this gap by integrating iPSC-derived microglia into neural organoids, thereby creating an immunized microenvironment that more accurately reflects human central neural tissue. This review explores the latest developments in this field, emphasizing the interaction between microglia and neurons within immunized neural organoids and highlights how this integrated approach not only enhances our understanding of neuroinflammatory processes but also opens new avenues in regenerative medicine. Full article

(This article belongs to the Special Issue Stem Cells and Regenerative Medicine: In Vitro and In Vivo Studies)

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