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Advances in Stem Cell Research for Future Therapies and In Vitro Disease Modelling

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 29869

Special Issue Editor

Dr. J. Carlos Villaescusa

E-Mail Website
Guest Editor
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Interests: regenerative medicine; stem cells; organoids; cell replacement therapies; neurodegeneration; neural stem cells; cardiomyocytes; retinal disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, stem cell therapy has become a very promising and advanced scientific research topic that is undergoing, now, its first clinical trials. This growing interest goes hand in hand with industrial partners aiming to bring technology and capacity up to scale and offer cell replacement therapies to patients suffering from chronic disorders.

This Special Issue is focused on recent discoveries that might contribute to the areas of basic stem cell research, in vitro disease modelling, translational stem cell research and stem cell therapies. Recent advances in cell reprogramming and genome editing technologies have created new possibilities for the development of new in vitro models to study human diseases. More recently, organoids have emerged as powerful tools to better study early developmental biology as a possible source for future cell therapies.

Cell-replacement therapies are now entering a new phase of growth and novel discoveries for cell differentiation, expansion, purification and delivery under GMP conditions are key aspects to move stem cell products from bench to bedside.

We invite you to contribute to this Special Issue and to communicate new advances in stem cell research for future therapies and in vitro disease modelling with original articles and reviews.

Dr. J. Carlos Villaescusa
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

  • embryonic stem cells
  • induced pluripotent stem cells
  • organoids
  • 3D cultures
  • organogenesis
  • in vitro disease modelling
  • developmental biology
  • cell fate
  • bioreactors
  • reprogramming
  • pluripotency
  • production and scalability
  • GMP adaptation
  • cell–material interaction
  • biomaterials
  • regenerative medicine
  • cell therapy
  • 3D scaffold
  • epigenetics

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Published Papers (7 papers)

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Research

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16 pages, 1928 KiB  
Article
Neurogenesis Is Increased in Human Neural Stem Cells by Aβ40 Peptide
by Adela Bernabeu-Zornoza, Raquel Coronel, Charlotte Palmer, Alberto Martín, Victoria López-Alonso and Isabel Liste
Int. J. Mol. Sci. 2022, 23(10), 5820; https://doi.org/10.3390/ijms23105820 - 22 May 2022
Cited by 10 | Viewed by 2988
Abstract
Amyloid-β 40 peptides [Aβ1-40 (Aβ40)] are present within amyloid plaques in the brains of patients with Alzheimer’s disease (AD). Even though Aβ peptides are considered neurotoxic, they can mediate many biological processes, both in adult brains and throughout brain development. However, the physiological [...] Read more.
Amyloid-β 40 peptides [Aβ1-40 (Aβ40)] are present within amyloid plaques in the brains of patients with Alzheimer’s disease (AD). Even though Aβ peptides are considered neurotoxic, they can mediate many biological processes, both in adult brains and throughout brain development. However, the physiological function of these Aβ peptides remains poorly understood, and the existing data are sometimes controversial. Here, we analyze and compare the effects of monomeric Aβ40 on the biology of differentiating human neural stem cells (human NSCs). For that purpose, we used a model of human NSCs called hNS1. Our data demonstrated that Aβ40 at high concentrations provokes apoptotic cellular death and the damage of DNA in human NSCs while also increasing the proliferation and favors neurogenesis by raising the percentage of proliferating neuronal precursors. These effects can be mediated, at least in part, by β-catenin. These results provide evidence of how Aβ modulate/regulate human NSC proliferation and differentiation, suggesting Aβ40 may be a pro-neurogenic factor. Our data could contribute to a better understanding of the molecular mechanisms involved in AD pathology and to the development of human NSC-based therapies for AD treatment, since these results could then be used in diagnosing the disease at early stages and be applied to the development of new treatment options. Full article
(This article belongs to the Special Issue Advances in Stem Cell Research for Future Therapies and In Vitro Disease Modelling)
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14 pages, 2184 KiB  
Article
Generation of Skeletal Muscle Organoids from Human Pluripotent Stem Cells to Model Myogenesis and Muscle Regeneration
by Min-Kyoung Shin, Jin Seok Bang, Jeoung Eun Lee, Hoang-Dai Tran, Genehong Park, Dong Ryul Lee and Junghyun Jo
Int. J. Mol. Sci. 2022, 23(9), 5108; https://doi.org/10.3390/ijms23095108 - 4 May 2022
Cited by 28 | Viewed by 8191
Abstract
In vitro organoids derived from human pluripotent stem cells (hPSCs) have been developed as essential tools to study the underlying mechanisms of human development and diseases owing to their structural and physiological similarity to corresponding organs. Despite recent advances, there are a few [...] Read more.
In vitro organoids derived from human pluripotent stem cells (hPSCs) have been developed as essential tools to study the underlying mechanisms of human development and diseases owing to their structural and physiological similarity to corresponding organs. Despite recent advances, there are a few methodologies for three-dimensional (3D) skeletal muscle differentiation, which focus on the terminal differentiation into myofibers and investigate the potential of modeling neuromuscular disorders and muscular dystrophies. However, these methodologies cannot recapitulate the developmental processes and lack regenerative capacity. In this study, we developed a new method to differentiate hPSCs into a 3D human skeletal muscle organoid (hSkMO). This organoid model could recapitulate the myogenesis process and possesses regenerative capacities of sustainable satellite cells (SCs), which are adult muscle stem/progenitor cells capable of self-renewal and myogenic differentiation. Our 3D model demonstrated myogenesis through the sequential occurrence of multiple myogenic cell types from SCs to myocytes. Notably, we detected quiescent, non-dividing SCs throughout the hSkMO differentiation in long-term culture. They were activated and differentiated to reconstitute muscle tissue upon damage. Thus, hSkMOs can recapitulate human skeletal muscle development and regeneration and may provide a new model for studying human skeletal muscles and related diseases. Full article
(This article belongs to the Special Issue Advances in Stem Cell Research for Future Therapies and In Vitro Disease Modelling)
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15 pages, 2242 KiB  
Article
NPFF Decreases Activity of Human Arcuate NPY Neurons: A Study in Embryonic-Stem-Cell-Derived Model
by Lola Torz, Kristoffer Niss, Sofia Lundh, Jens C. Rekling, Carlos Damian Quintana, Signe Emilie Dannulat Frazier, Aaron J. Mercer, Anda Cornea, Charlotte Vinther Bertelsen, Marina Kjærgaard Gerstenberg, Ann Maria Kruse Hansen, Mette Guldbrandt, Jens Lykkesfeldt, Linu Mary John, J. Carlos Villaescusa and Natalia Petersen
Int. J. Mol. Sci. 2022, 23(6), 3260; https://doi.org/10.3390/ijms23063260 - 17 Mar 2022
Cited by 9 | Viewed by 3546
Abstract
Restoring the control of food intake is the key to obesity management and prevention. The arcuate nucleus (ARC) of the hypothalamus is extensively being studied as a potential anti-obesity target. Animal studies showed that neuropeptide FF (NPFF) reduces food intake by its action [...] Read more.
Restoring the control of food intake is the key to obesity management and prevention. The arcuate nucleus (ARC) of the hypothalamus is extensively being studied as a potential anti-obesity target. Animal studies showed that neuropeptide FF (NPFF) reduces food intake by its action in neuropeptide Y (NPY) neurons of the hypothalamic ARC, but the detailed mode of action observed in human neurons is missing, due to the lack of a human-neuron-based model for pharmacology testing. Here, we validated and utilized a human-neural-stem-cell-based (hNSC) model of ARC to test the effects of NPFF on cellular pathways and neuronal activity. We found that in the human neurons, decreased cAMP levels by NPFF resulted in a reduced rate of cytoplasmic calcium oscillations, indicating an inhibition of ARC NPY neurons. This suggests the therapeutic potential of NPFFR2 in obesity. In addition, we demonstrate the use of human-stem-cell-derived neurons in pharmacological applications and the potential of this model to address functional aspects of human hypothalamic neurons. Full article
(This article belongs to the Special Issue Advances in Stem Cell Research for Future Therapies and In Vitro Disease Modelling)
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13 pages, 2829 KiB  
Article
Secretome from Human Mesenchymal Stem Cells-Derived Endothelial Cells Promotes Wound Healing in a Type-2 Diabetes Mouse Model
by Valeska Ormazabal, Estefanía Nova-Lampeti, Daniela Rojas, Felipe A. Zúñiga, Carlos Escudero, Paola Lagos, Alexa Moreno, Yanara Pavez, Camila Reyes, Milly Yáñez, Mabel Vidal, Guillermo Cabrera-Vives, Katherine Oporto and Claudio Aguayo
Int. J. Mol. Sci. 2022, 23(2), 941; https://doi.org/10.3390/ijms23020941 - 15 Jan 2022
Cited by 18 | Viewed by 4202
Abstract
Tissue regeneration is often impaired in patients with metabolic disorders such as diabetes mellitus and obesity, exhibiting reduced wound repair and limited regeneration capacity. We and others have demonstrated that wound healing under normal metabolic conditions is potentiated by the secretome of human [...] Read more.
Tissue regeneration is often impaired in patients with metabolic disorders such as diabetes mellitus and obesity, exhibiting reduced wound repair and limited regeneration capacity. We and others have demonstrated that wound healing under normal metabolic conditions is potentiated by the secretome of human endothelial cell-differentiated mesenchymal stem cells (hMSC-EC). However, it is unknown whether this effect is sustained under hyperglycemic conditions. In this study, the wound healing effect of secretomes from undifferentiated human mesenchymal stem cells (hMSC) and hMSC-EC in a type-2 diabetes mouse model was analyzed. hMSC were isolated from human Wharton’s jelly and differentiated into hMSC-EC. hMSC and hMSC-EC secretomes were analyzed and their wound healing capacity in C57Bl/6J mice fed with control (CD) or high fat diet (HFD) was evaluated. Our results showed that hMSC-EC secretome enhanced endothelial cell proliferation and wound healing in vivo when compared with hMSC secretome. Five soluble proteins (angiopoietin-1, angiopoietin-2, Factor de crecimiento fibroblástico, Matrix metallopeptidase 9, and Vascular Endothelial Growth Factor) were enriched in hMSC-EC secretome in comparison to hMSC secretome. Thus, the five recombinant proteins were mixed, and their pro-healing property was evaluated in vitro and in vivo. Functional analysis demonstrated that a cocktail of these proteins enhanced the wound healing process similar to hMSC-EC secretome in HFD mice. Overall, our results show that hMSC-EC secretome or a combination of specific proteins enriched in the hMSC-EC secretome enhanced wound healing process under hyperglycemic conditions. Full article
(This article belongs to the Special Issue Advances in Stem Cell Research for Future Therapies and In Vitro Disease Modelling)
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13 pages, 3029 KiB  
Article
Macrophages Modulate the Function of MSC- and iPSC-Derived Fibroblasts in the Presence of Polyethylene Particles
by Qi Gao, Zhong Li, Claire Rhee, Shiqi Xiang, Masahiro Maruyama, Elijah Ejun Huang, Zhenyu Yao, Bruce A. Bunnell, Rocky S. Tuan, Hang Lin, Michael S. Gold and Stuart B. Goodman
Int. J. Mol. Sci. 2021, 22(23), 12837; https://doi.org/10.3390/ijms222312837 - 27 Nov 2021
Cited by 3 | Viewed by 3544
Abstract
Fibroblasts in the synovial membrane secrete molecules essential to forming the extracellular matrix (ECM) and supporting joint homeostasis. While evidence suggests that fibroblasts contribute to the response to joint injury, the outcomes appear to be patient-specific and dependent on interactions between resident immune [...] Read more.
Fibroblasts in the synovial membrane secrete molecules essential to forming the extracellular matrix (ECM) and supporting joint homeostasis. While evidence suggests that fibroblasts contribute to the response to joint injury, the outcomes appear to be patient-specific and dependent on interactions between resident immune cells, particularly macrophages (Mφs). On the other hand, the response of Mφs to injury depends on their functional phenotype. The goal of these studies was to further explore these issues in an in vitro 3D microtissue model that simulates a pathophysiological disease-specific microenvironment. Two sources of fibroblasts were used to assess patient-specific influences: mesenchymal stem cell (MSC)- and induced pluripotent stem cell (iPSC)-derived fibroblasts. These were co-cultured with either M1 or M2 Mφs, and the cultures were challenged with polyethylene particles coated with lipopolysaccharide (cPE) to model wear debris generated from total joint arthroplasties. Our results indicated that the fibroblast response to cPE was dependent on the source of the fibroblasts and the presence of M1 or M2 Mφs: the fibroblast response as measured by gene expression changes was amplified by the presence of M2 Mφs. These results demonstrate that the immune system modulates the function of fibroblasts; furthermore, different sources of differentiated fibroblasts may lead to divergent results. Overall, our research suggests that M2 Mφs may be a critical target for the clinical treatment of cPE induced fibrosis. Full article
(This article belongs to the Special Issue Advances in Stem Cell Research for Future Therapies and In Vitro Disease Modelling)
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18 pages, 16606 KiB  
Article
Oligomeric and Fibrillar Species of Aβ42 Diversely Affect Human Neural Stem Cells
by Adela Bernabeu-Zornoza, Raquel Coronel, Charlotte Palmer, Victoria López-Alonso and Isabel Liste
Int. J. Mol. Sci. 2021, 22(17), 9537; https://doi.org/10.3390/ijms22179537 - 2 Sep 2021
Cited by 6 | Viewed by 2480
Abstract
Amyloid-β 42 peptide (Aβ1-42 (Aβ42)) is well-known for its involvement in the development of Alzheimer’s disease (AD). Aβ42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity; however, like other forms of Aβ peptide, [...] Read more.
Amyloid-β 42 peptide (Aβ1-42 (Aβ42)) is well-known for its involvement in the development of Alzheimer’s disease (AD). Aβ42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity; however, like other forms of Aβ peptide, the role of these peptides remains unclear. Here we analyze and compare the effects of oligomeric and fibrillary Aβ42 peptide on the biology (cell death, proliferative rate, and cell fate specification) of differentiating human neural stem cells (hNS1 cell line). By using the hNS1 cells we found that, at high concentrations, oligomeric and fibrillary Aβ42 peptides provoke apoptotic cellular death and damage of DNA in these cells, but Aβ42 fibrils have the strongest effect. The data also show that both oligomeric and fibrillar Aβ42 peptides decrease cellular proliferation but Aβ42 oligomers have the greatest effect. Finally, both, oligomers and fibrils favor gliogenesis and neurogenesis in hNS1 cells, although, in this case, the effect is more prominent in oligomers. All together the findings of this study may contribute to a better understanding of the molecular mechanisms involved in the pathology of AD and to the development of human neural stem cell-based therapies for AD treatment. Full article
(This article belongs to the Special Issue Advances in Stem Cell Research for Future Therapies and In Vitro Disease Modelling)
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Review

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14 pages, 1130 KiB  
Review
Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development
by Jacopo Meldolesi
Int. J. Mol. Sci. 2022, 23(2), 625; https://doi.org/10.3390/ijms23020625 - 6 Jan 2022
Cited by 7 | Viewed by 3367
Abstract
Stem cells, identified several decades ago, started to attract interest at the end of the nineties when families of mesenchymal stem cells (MSCs), concentrated in the stroma of most organs, were found to participate in the therapy of many diseases. In cancer, however, [...] Read more.
Stem cells, identified several decades ago, started to attract interest at the end of the nineties when families of mesenchymal stem cells (MSCs), concentrated in the stroma of most organs, were found to participate in the therapy of many diseases. In cancer, however, stem cells of high importance are specific to another family, the cancer stem cells (CSCs). This comprehensive review is focused on the role and the mechanisms of CSCs and of their specific extracellular vesicles (EVs), which are composed of both exosomes and ectosomes. Compared to non-stem (normal) cancer cells, CSCs exist in small populations that are preferentially distributed to the niches, such as minor specific tissue sites corresponding to the stroma of non-cancer tissues. At niches and marginal sites of other cancer masses, the tissue exhibits peculiar properties that are typical of the tumor microenvironment (TME) of cancers. The extracellular matrix (ECM) includes components different from non-cancer tissues. CSCs and their EVs, in addition to effects analogous to those of MSCs/EVs, participate in processes of key importance, specific to cancer: generation of distinct cell subtypes, proliferation, differentiation, progression, formation of metastases, immune and therapy resistance, cancer relapse. Many of these, and other, effects require CSC cooperation with surrounding cells, especially MSCs. Filtered non-cancer cells, especially macrophages and fibroblasts, contribute to collaborative cancer transition/integration processes. Therapy developments are mentioned as ongoing preclinical initiatives. The preliminary state of clinical medicine is presented in terms of both industrial development and future treatments. The latter will be administered to specific patients together with known drugs, with the aim of eradicating their tumor growth and metastases. Full article
(This article belongs to the Special Issue Advances in Stem Cell Research for Future Therapies and In Vitro Disease Modelling)
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