Cells

Editorial

3 pages, 205 KiB

Open AccessEditorial

Fundamental and Applied Advances in Stem Cell Therapeutic Research

by Makram Merimi, Saida Rahmani, Ahmed Afailal Tribak, Fatima Bouhtit, Hassan Fahmi and Mehdi Najar

Cells 2022, 11(12), 1976; https://doi.org/10.3390/cells11121976 - 20 Jun 2022

Viewed by 1858

Abstract

We are pleased to present this Special Issue of Cells, entitled ‘Feature Papers in Stem Cells’ [...] Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

Research

Jump to: Editorial, Review, Other

13 pages, 2691 KiB

Open AccessArticle

Functional Characterization of Endothelial Cells Differentiated from Porcine Epiblast Stem Cells

by Joon-Hong Shin, Bo-Gyeong Seo, In-Won Lee, Hyo-Jin Kim, Eun-Chan Seo, Kwang-Min Lee, Soo-Been Jeon, Sang-Ki Baek, Tae-Suk Kim, Jeong-Hyung Lee, Jung-Woo Choi, Cheol Hwangbo and Joon-Hee Lee

Cells 2022, 11(9), 1524; https://doi.org/10.3390/cells11091524 - 2 May 2022

Cited by 7 | Viewed by 3247

Abstract

Endothelial cells (ECs), lining blood vessels’ lumen, play an essential role in regulating vascular functions. As multifunctional components of vascular structures, pluripotent stem cells (PSCs) are the promising source for potential therapeutic applications in various vascular diseases. Our laboratory has previously established an [...] Read more.

Endothelial cells (ECs), lining blood vessels’ lumen, play an essential role in regulating vascular functions. As multifunctional components of vascular structures, pluripotent stem cells (PSCs) are the promising source for potential therapeutic applications in various vascular diseases. Our laboratory has previously established an approach for differentiating porcine epiblast stem cells (pEpiSCs) into ECs, representing an alternative and potentially superior cell source. However, the condition of pEpiSCs-derived ECs growth has yet to be determined, and whether pEpiSCs differentiate into functional ECs remained unclear. Changes in morphology, proliferation and functional endothelial marker were assessed in pEpiSCs-derived ECs in vitro. pEpiSCs-derived ECs were subjected to magnetic-activated cell sorting (MACS) to collect CD-31+ of ECs. We found that sorted ECs showed the highest proliferation rate in differentiation media in primary culture and M199 media in the subculture. Next, sorted ECs were examined for their ability to act as typical vascular ECs through capillary-like structure formation assay, Dil-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake, and three-dimensional spheroid sprouting. Consequently, pEpiSCs-derived ECs function as typical vascular ECs, indicating that pEpiSC-derived ECs might be used to develop cell therapeutics for vascular disease. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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13 pages, 2053 KiB

Open AccessArticle

Tet1 Suppresses p21 to Ensure Proper Cell Cycle Progression in Embryonic Stem Cells

by Stephanie Chrysanthou, Julio C. Flores and Meelad M. Dawlaty

Cells 2022, 11(8), 1366; https://doi.org/10.3390/cells11081366 - 17 Apr 2022

Cited by 11 | Viewed by 3189

Abstract

Ten eleven translocation 1 (Tet1) is a DNA dioxygenase that promotes DNA demethylation by oxidizing 5-methylcytosine. It can also partner with chromatin-activating and repressive complexes to regulate gene expressions independent of its enzymatic activity. Tet1 is highly expressed in embryonic stem cells (ESCs) [...] Read more.

Ten eleven translocation 1 (Tet1) is a DNA dioxygenase that promotes DNA demethylation by oxidizing 5-methylcytosine. It can also partner with chromatin-activating and repressive complexes to regulate gene expressions independent of its enzymatic activity. Tet1 is highly expressed in embryonic stem cells (ESCs) and regulates pluripotency and differentiation. However, its roles in ESC cell cycle progression and proliferation have not been investigated. Using a series of Tet1 catalytic mutant (Tet1^m^/m), knockout (Tet1^−/−) and wild type (Tet1^+/+) mouse ESCs (mESCs), we identified a non-catalytic role of Tet1 in the proper cell cycle progression and proliferation of mESCs. Tet1^−/−, but not Tet1^m^/m, mESCs exhibited a significant reduction in proliferation and delayed progression through G1. We found that the cyclin-dependent kinase inhibitor p21/Cdkn1a was uniquely upregulated in Tet1^−/− mESCs and its knockdown corrected the slow proliferation and delayed G1 progression. Mechanistically, we found that p21 was a direct target of Tet1. Tet1 occupancy at the p21 promoter overlapped with the repressive histone mark H3K27me3 as well as with the H3K27 trimethyl transferase PRC2 component Ezh2. A loss of Tet1, but not loss of its catalytic activity, significantly reduced the enrichment of Ezh2 and H3K27 trimethylation at the p21 promoter without affecting the DNA methylation levels. We also found that the proliferation defects of Tet1^−/− mESCs were independent of their differentiation defects. Together, these findings established a non-catalytic role for Tet1 in suppressing p21 in mESCs to ensure a rapid G1-to-S progression, which is a key hallmark of ESC proliferation. It also established Tet1 as an epigenetic regulator of ESC proliferation in addition to its previously defined roles in ESC pluripotency and differentiation. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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20 pages, 2227 KiB

Open AccessArticle

Myogenic Precursor Cells Show Faster Activation and Enhanced Differentiation in a Male Mouse Model Selected for Advanced Endurance Exercise Performance

by Stefan Petkov, Julia Brenmoehl, Martina Langhammer, Andreas Hoeflich and Monika Röntgen

Cells 2022, 11(6), 1001; https://doi.org/10.3390/cells11061001 - 16 Mar 2022

Cited by 6 | Viewed by 2809

Abstract

Satellite cells (SATC), the most abundant skeletal muscle stem cells, play a main role in muscle plasticity, including the adaptive response following physical activity. Thus, we investigated how long-term phenotype selection of male mice for high running performance (Dummerstorf high Treadmill Performance; DUhTP) [...] Read more.

Satellite cells (SATC), the most abundant skeletal muscle stem cells, play a main role in muscle plasticity, including the adaptive response following physical activity. Thus, we investigated how long-term phenotype selection of male mice for high running performance (Dummerstorf high Treadmill Performance; DUhTP) affects abundance, creatine kinase activity, myogenic marker expression (Pax7, MyoD), and functionality (growth kinetics, differentiation) of SATC and their progeny. SATC were isolated from sedentary male DUhTP and control (Dummerstorf Control; DUC) mice at days 12, 43, and 73 of life and after voluntary wheel running for three weeks (day 73). Marked line differences occur at days 43 and 73 (after activity). At both ages, analysis of SATC growth via xCELLigence system revealed faster activation accompanied by a higher proliferation rate and lower proportion of Pax7+ cells in DUhTP mice, indicating reduced reserve cell formation and faster transition into differentiation. Cultures from sedentary DUhTP mice contain an elevated proportion of actively proliferating Pax7+/MyoD+ cells and have a higher fusion index leading to the formation of more large and very large myotubes at day 43. This robust hypertrophic response occurs without any functional load in the donor mice. Thus, our selection model seems to recruit myogenic precursor cells/SATC with a lower activation threshold that respond more rapidly to external stimuli and are more primed for differentiation at the expense of more primitive cells. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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21 pages, 3393 KiB

Open AccessArticle

Zscan4 Contributes to Telomere Maintenance in Telomerase-Deficient Late Generation Mouse ESCs and Human ALT Cancer Cells

by Jiameng Dan, Zhongcheng Zhou, Fang Wang, Hua Wang, Renpeng Guo, David L. Keefe and Lin Liu

Cells 2022, 11(3), 456; https://doi.org/10.3390/cells11030456 - 28 Jan 2022

Cited by 13 | Viewed by 3788

Abstract

Proper telomere length is essential for indefinite self-renewal of embryonic stem (ES) cells and cancer cells. Telomerase-deficient late generation mouse ES cells and human ALT cancer cells are able to propagate for numerous passages, suggesting telomerase-independent mechanisms responding for telomere maintenance. However, the [...] Read more.

Proper telomere length is essential for indefinite self-renewal of embryonic stem (ES) cells and cancer cells. Telomerase-deficient late generation mouse ES cells and human ALT cancer cells are able to propagate for numerous passages, suggesting telomerase-independent mechanisms responding for telomere maintenance. However, the underlying mechanisms ensuring the telomere length maintenance are unclear. Here, using late generation telomerase KO (G4 Terc^-/-) ESCs as a model, we show that Zscan4, highly upregulated in G4 Terc^-/- ESCs, is responsible for the prolonged culture of these cells with stably short telomeres. Mechanistically, G4 Terc^-/- ESCs showed reduced levels of DNA methylation and H3K9me3 at Zscan4 promoter and subtelomeres, which relieved the expression of Zscan4. Similarly, human ZSCAN4 was also derepressed by reduced H3K9me3 at its promoter in ALT U2 OS cells, and depletion of ZSCAN4 significantly shortened telomeres. Our results define a similar conserved pathway contributing to the telomere maintenance in telomerase-deficient late generation mESCs and human ALT U2OS cancer cells. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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24 pages, 14860 KiB

Open AccessArticle

Synaptic Hyaluronan Synthesis and CD44-Mediated Signaling Coordinate Neural Circuit Development

by Emily S. Wilson and Karen Litwa

Cells 2021, 10(10), 2574; https://doi.org/10.3390/cells10102574 - 28 Sep 2021

Cited by 6 | Viewed by 4438

Abstract

The hyaluronan-based extracellular matrix is expressed throughout nervous system development and is well-known for the formation of perineuronal nets around inhibitory interneurons. Since perineuronal nets form postnatally, the role of hyaluronan in the initial formation of neural circuits remains unclear. Neural circuits emerge [...] Read more.

The hyaluronan-based extracellular matrix is expressed throughout nervous system development and is well-known for the formation of perineuronal nets around inhibitory interneurons. Since perineuronal nets form postnatally, the role of hyaluronan in the initial formation of neural circuits remains unclear. Neural circuits emerge from the coordinated electrochemical signaling of excitatory and inhibitory synapses. Hyaluronan localizes to the synaptic cleft of developing excitatory synapses in both human cortical spheroids and the neonatal mouse brain and is diminished in the adult mouse brain. Given this developmental-specific synaptic localization, we sought to determine the mechanisms that regulate hyaluronan synthesis and signaling during synapse formation. We demonstrate that hyaluronan synthase-2, HAS2, is sufficient to increase hyaluronan levels in developing neural circuits of human cortical spheroids. This increased hyaluronan production reduces excitatory synaptogenesis, promotes inhibitory synaptogenesis, and suppresses action potential formation. The hyaluronan receptor, CD44, promotes hyaluronan retention and suppresses excitatory synaptogenesis through regulation of RhoGTPase signaling. Our results reveal mechanisms of hyaluronan synthesis, retention, and signaling in developing neural circuits, shedding light on how disease-associated hyaluronan alterations can contribute to synaptic defects. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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16 pages, 8126 KiB

Open AccessArticle

Evaluation of the Effects of Human Dental Pulp Stem Cells on the Biological Phenotype of Hypertrophic Keloid Fibroblasts

by Ming Yan, Ling-Ling Fu, Ola A. Nada, Li-Ming Chen, Martin Gosau, Ralf Smeets, Hong-Chao Feng and Reinhard E. Friedrich

Cells 2021, 10(7), 1803; https://doi.org/10.3390/cells10071803 - 16 Jul 2021

Cited by 5 | Viewed by 2895

Abstract

Objective: Despite numerous existing treatments for keloids, the responses in the clinic have been disappointing, due to either low efficacy or side effects. Numerous studies dealing with preclinical and clinical trials have been published about effective therapies for fibrotic diseases using mesenchymal stem [...] Read more.

Objective: Despite numerous existing treatments for keloids, the responses in the clinic have been disappointing, due to either low efficacy or side effects. Numerous studies dealing with preclinical and clinical trials have been published about effective therapies for fibrotic diseases using mesenchymal stem cells; however, no research has yet been reported to scientifically investigate the effect of human dental pulp stem cells (HDPSCs) on the treatment of keloids. The objective is to provide an experimental basis for the application of stem cells in the treatment of keloids. Methods: Human normal fibroblasts (HNFs) and human keloid fibroblasts (HKFs) were cultured alone and in combination with HDPSCs using a transwell cell-contact-independent cell culture system. The effects of HDPSCs on HKFs were tested using a CCK-8 assay, live/dead staining assay, quantitative polymerase chain reaction, Western blot and immunofluorescence microscopy. Results: HDPSCs did not inhibit the proliferation nor the apoptosis of HKFs and HNFs. HDPSCs did, however, inhibit their migration. Furthermore, HDPSCs significantly decreased the expression of profibrotic genes (CTGF, TGF-β1 and TGF-β2) in HKFs and KNFs (p < 0.05), except for CTGF in HNFs. Moreover, HDPSCs suppressed the extracellular matrix (ECM) synthesis in HKFs, as indicated by the decreased expression of collagen I as well as the low levels of hydroxyproline in the cell culture supernatant (p < 0.05). Conclusions: The co-culture of HDPSCs inhibits the migration of HKFs and the expression of pro-fibrotic genes, while promoting the expression of anti-fibrotic genes. HDPSCs’ co-culture also inhibits the synthesis of the extracellular matrix by HKFs, whereas it does not affect the proliferation and apoptosis of HKFs. Therefore, it can be concluded that HDPSCs can themselves be used as a tool for restraining/hindering the initiation or progression of fibrotic tissue. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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23 pages, 5969 KiB

Open AccessArticle

Tissue-Specific Microparticles Improve Organoid Microenvironment for Efficient Maturation of Pluripotent Stem-Cell-Derived Hepatocytes

by Ensieh Zahmatkesh, Mohammad Hossein Ghanian, Ibrahim Zarkesh, Zahra Farzaneh, Majid Halvaei, Zahra Heydari, Farideh Moeinvaziri, Amnah Othman, Marc Ruoß, Abbas Piryaei, Roberto Gramignoli, Saeed Yakhkeshi, Andreas Nüssler, Mustapha Najimi, Hossein Baharvand and Massoud Vosough

Cells 2021, 10(6), 1274; https://doi.org/10.3390/cells10061274 - 21 May 2021

Cited by 23 | Viewed by 5489

Abstract

Liver organoids (LOs) are receiving considerable attention for their potential use in drug screening, disease modeling, and transplantable constructs. Hepatocytes, as the key component of LOs, are isolated from the liver or differentiated from pluripotent stem cells (PSCs). PSC-derived hepatocytes are preferable because [...] Read more.

Liver organoids (LOs) are receiving considerable attention for their potential use in drug screening, disease modeling, and transplantable constructs. Hepatocytes, as the key component of LOs, are isolated from the liver or differentiated from pluripotent stem cells (PSCs). PSC-derived hepatocytes are preferable because of their availability and scalability. However, efficient maturation of the PSC-derived hepatocytes towards functional units in LOs remains a challenging subject. The incorporation of cell-sized microparticles (MPs) derived from liver extracellular matrix (ECM), could provide an enriched tissue-specific microenvironment for further maturation of hepatocytes inside the LOs. In the present study, the MPs were fabricated by chemical cross-linking of a water-in-oil dispersion of digested decellularized sheep liver. These MPs were mixed with human PSC-derived hepatic endoderm, human umbilical vein endothelial cells, and mesenchymal stromal cells to produce homogenous bioengineered LOs (BLOs). This approach led to the improvement of hepatocyte-like cells in terms of gene expression and function, CYP activities, albumin secretion, and metabolism of xenobiotics. The intraperitoneal transplantation of BLOs in an acute liver injury mouse model led to an enhancement in survival rate. Furthermore, efficient hepatic maturation was demonstrated after ex ovo transplantation. In conclusion, the incorporation of cell-sized tissue-specific MPs in BLOs improved the maturation of human PSC-derived hepatocyte-like cells compared to LOs. This approach provides a versatile strategy to produce functional organoids from different tissues and offers a novel tool for biomedical applications. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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Review

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18 pages, 1322 KiB

Open AccessFeature PaperReview

Potential of Fibrin Glue and Mesenchymal Stem Cells (MSCs) to Regenerate Nerve Injuries: A Systematic Review

by Adriana de Cássia Ortiz, Simone Ortiz Moura Fideles, Karina Torres Pomini, Márcia Zilioli Bellini, Eliana de Souza Bastos Mazuqueli Pereira, Carlos Henrique Bertoni Reis, João Paulo Galletti Pilon, Miguel Ângelo de Marchi, Beatriz Flavia de Moraes Trazzi, Willian Saranholi da Silva, Marcelo Rodrigues da Cunha, Daniela Vieira Buchaim and Rogerio Leone Buchaim

Cells 2022, 11(2), 221; https://doi.org/10.3390/cells11020221 - 10 Jan 2022

Cited by 19 | Viewed by 3358

Abstract

Cell-based therapy is a promising treatment to favor tissue healing through less invasive strategies. Mesenchymal stem cells (MSCs) highlighted as potential candidates due to their angiogenic, anti-apoptotic and immunomodulatory properties, in addition to their ability to differentiate into several specialized cell lines. Cells [...] Read more.

Cell-based therapy is a promising treatment to favor tissue healing through less invasive strategies. Mesenchymal stem cells (MSCs) highlighted as potential candidates due to their angiogenic, anti-apoptotic and immunomodulatory properties, in addition to their ability to differentiate into several specialized cell lines. Cells can be carried through a biological delivery system, such as fibrin glue, which acts as a temporary matrix that favors cell-matrix interactions and allows local and paracrine functions of MSCs. Thus, the aim of this systematic review was to evaluate the potential of fibrin glue combined with MSCs in nerve regeneration. The bibliographic search was performed in the PubMed/MEDLINE, Web of Science and Embase databases, using the descriptors (“fibrin sealant” OR “fibrin glue”) AND “stem cells” AND “nerve regeneration”, considering articles published until 2021. To compose this review, 13 in vivo studies were selected, according to the eligibility criteria. MSCs favored axonal regeneration, remyelination of nerve fibers, as well as promoted an increase in the number of myelinated fibers, myelin sheath thickness, number of axons and expression of growth factors, with significant improvement in motor function recovery. This systematic review showed clear evidence that fibrin glue combined with MSCs has the potential to regenerate nervous system lesions. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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18 pages, 3101 KiB

Open AccessReview

Roles of Mesenchymal Cells in the Lung: From Lung Development to Chronic Obstructive Pulmonary Disease

by Amel Nasri, Florent Foisset, Engi Ahmed, Zakaria Lahmar, Isabelle Vachier, Christian Jorgensen, Said Assou, Arnaud Bourdin and John De Vos

Cells 2021, 10(12), 3467; https://doi.org/10.3390/cells10123467 - 9 Dec 2021

Cited by 24 | Viewed by 6393

Abstract

Mesenchymal cells are an essential cell type because of their role in tissue support, their multilineage differentiation capacities and their potential clinical applications. They play a crucial role during lung development by interacting with airway epithelium, and also during lung regeneration and remodeling [...] Read more.

Mesenchymal cells are an essential cell type because of their role in tissue support, their multilineage differentiation capacities and their potential clinical applications. They play a crucial role during lung development by interacting with airway epithelium, and also during lung regeneration and remodeling after injury. However, much less is known about their function in lung disease. In this review, we discuss the origins of mesenchymal cells during lung development, their crosstalk with the epithelium, and their role in lung diseases, particularly in chronic obstructive pulmonary disease. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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28 pages, 2387 KiB

Open AccessReview

Tissue-Nonspecific Alkaline Phosphatase, a Possible Mediator of Cell Maturation: Towards a New Paradigm

by Masahiro Sato, Issei Saitoh, Yuki Kiyokawa, Yoko Iwase, Naoko Kubota, Natsumi Ibano, Hirofumi Noguchi, Youichi Yamasaki and Emi Inada

Cells 2021, 10(12), 3338; https://doi.org/10.3390/cells10123338 - 28 Nov 2021

Cited by 12 | Viewed by 6721

Abstract

Alkaline phosphatase (ALP) is a ubiquitous membrane-bound glycoprotein capable of providing inorganic phosphate by catalyzing the hydrolysis of organic phosphate esters, or removing inorganic pyrophosphate that inhibits calcification. In humans, four forms of ALP cDNA have been cloned, among which tissue-nonspecific ALP (TNSALP) [...] Read more.

Alkaline phosphatase (ALP) is a ubiquitous membrane-bound glycoprotein capable of providing inorganic phosphate by catalyzing the hydrolysis of organic phosphate esters, or removing inorganic pyrophosphate that inhibits calcification. In humans, four forms of ALP cDNA have been cloned, among which tissue-nonspecific ALP (TNSALP) (TNSALP) is widely distributed in the liver, bone, and kidney, making it an important marker in clinical and basic research. Interestingly, TNSALP is highly expressed in juvenile cells, such as pluripotent stem cells (i.e., embryonic stem cells and induced pluripotent stem cells (iPSCs)) and somatic stem cells (i.e., neuronal stem cells and bone marrow mesenchymal stem cells). Hypophosphatasia is a genetic disorder causing defects in bone and tooth development as well as neurogenesis. Mutations in the gene coding for TNSALP are thought to be responsible for the abnormalities, suggesting the essential role of TNSALP in these events. Moreover, a reverse-genetics-based study using mice revealed that TNSALP is important in bone and tooth development as well as neurogenesis. However, little is known about the role of TNSALP in the maintenance and differentiation of juvenile cells. Recently, it was reported that cells enriched with TNSALP are more easily reprogrammed into iPSCs than those with less TNSALP. Furthermore, in bone marrow stem cells, ALP could function as a “signal regulator” deciding the fate of these cells. In this review, we summarize the properties of ALP and the background of ALP gene analysis and its manipulation, with a special focus on the potential role of TNSALP in the generation (and possibly maintenance) of juvenile cells. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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35 pages, 8414 KiB

Open AccessReview

Recent Advances in Cardiac Tissue Engineering for the Management of Myocardium Infarction

by Vineeta Sharma, Sanat Kumar Dash, Kavitha Govarthanan, Rekha Gahtori, Nidhi Negi, Mahmood Barani, Richa Tomar, Sudip Chakraborty, Santosh Mathapati, Dillip Kumar Bishi, Poonam Negi, Kamal Dua, Sachin Kumar Singh, Rohit Gundamaraju, Abhijit Dey, Janne Ruokolainen, Vijay Kumar Thakur, Kavindra Kumar Kesari, Niraj Kumar Jha, Piyush Kumar Gupta and Shreesh Ojha Show full author list Hide full author list

Cells 2021, 10(10), 2538; https://doi.org/10.3390/cells10102538 - 25 Sep 2021

Cited by 27 | Viewed by 8601

Abstract

Myocardium Infarction (MI) is one of the foremost cardiovascular diseases (CVDs) causing death worldwide, and its case numbers are expected to continuously increase in the coming years. Pharmacological interventions have not been at the forefront in ameliorating MI-related morbidity and mortality. Stem cell-based [...] Read more.

Myocardium Infarction (MI) is one of the foremost cardiovascular diseases (CVDs) causing death worldwide, and its case numbers are expected to continuously increase in the coming years. Pharmacological interventions have not been at the forefront in ameliorating MI-related morbidity and mortality. Stem cell-based tissue engineering approaches have been extensively explored for their regenerative potential in the infarcted myocardium. Recent studies on microfluidic devices employing stem cells under laboratory set-up have revealed meticulous events pertaining to the pathophysiology of MI occurring at the infarcted site. This discovery also underpins the appropriate conditions in the niche for differentiating stem cells into mature cardiomyocyte-like cells and leads to engineering of the scaffold via mimicking of native cardiac physiological conditions. However, the mode of stem cell-loaded engineered scaffolds delivered to the site of infarction is still a challenging mission, and yet to be translated to the clinical setting. In this review, we have elucidated the various strategies developed using a hydrogel-based system both as encapsulated stem cells and as biocompatible patches loaded with cells and applied at the site of infarction. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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45 pages, 6239 KiB

Open AccessFeature PaperReview

Insight into Hypoxia Stemness Control

by Miriam Di Mattia, Annunziata Mauro, Maria Rita Citeroni, Beatrice Dufrusine, Alessia Peserico, Valentina Russo, Paolo Berardinelli, Enrico Dainese, Annamaria Cimini and Barbara Barboni

Cells 2021, 10(8), 2161; https://doi.org/10.3390/cells10082161 - 22 Aug 2021

Cited by 15 | Viewed by 6160

Abstract

Recently, the research on stemness and multilineage differentiation mechanisms has greatly increased its value due to the potential therapeutic impact of stem cell-based approaches. Stem cells modulate their self-renewing and differentiation capacities in response to endogenous and/or extrinsic factors that can control stem [...] Read more.

Recently, the research on stemness and multilineage differentiation mechanisms has greatly increased its value due to the potential therapeutic impact of stem cell-based approaches. Stem cells modulate their self-renewing and differentiation capacities in response to endogenous and/or extrinsic factors that can control stem cell fate. One key factor controlling stem cell phenotype is oxygen (O₂). Several pieces of evidence demonstrated that the complexity of reproducing O₂ physiological tensions and gradients in culture is responsible for defective stem cell behavior in vitro and after transplantation. This evidence is still worsened by considering that stem cells are conventionally incubated under non-physiological air O₂ tension (21%). Therefore, the study of mechanisms and signaling activated at lower O₂ tension, such as those existing under native microenvironments (referred to as hypoxia), represent an effective strategy to define if O₂ is essential in preserving naïve stemness potential as well as in modulating their differentiation. Starting from this premise, the goal of the present review is to report the status of the art about the link existing between hypoxia and stemness providing insight into the factors/molecules involved, to design targeted strategies that, recapitulating naïve O₂ signals, enable towards the therapeutic use of stem cell for tissue engineering and regenerative medicine. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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23 pages, 2403 KiB

Open AccessReview

Human Granulosa Cells—Stemness Properties, Molecular Cross-Talk and Follicular Angiogenesis

by Claudia Dompe, Magdalena Kulus, Katarzyna Stefańska, Wiesława Kranc, Błażej Chermuła, Rut Bryl, Wojciech Pieńkowski, Mariusz J. Nawrocki, James N. Petitte, Bogusława Stelmach, Paul Mozdziak, Michal Jeseta, Leszek Pawelczyk, Jędrzej M. Jaśkowski, Hanna Piotrowska-Kempisty, Robert Z. Spaczyński, Michał Nowicki and Bartosz Kempisty

Cells 2021, 10(6), 1396; https://doi.org/10.3390/cells10061396 - 5 Jun 2021

Cited by 52 | Viewed by 10246

Abstract

The ovarian follicle is the basic functional unit of the ovary, comprising theca cells and granulosa cells (GCs). Two different types of GCs, mural GCs and cumulus cells (CCs), serve different functions during folliculogenesis. Mural GCs produce oestrogen during the follicular phase and [...] Read more.

The ovarian follicle is the basic functional unit of the ovary, comprising theca cells and granulosa cells (GCs). Two different types of GCs, mural GCs and cumulus cells (CCs), serve different functions during folliculogenesis. Mural GCs produce oestrogen during the follicular phase and progesterone after ovulation, while CCs surround the oocyte tightly and form the cumulus oophurus and corona radiata inner cell layer. CCs are also engaged in bi-directional metabolite exchange with the oocyte, as they form gap-junctions, which are crucial for both the oocyte’s proper maturation and GC proliferation. However, the function of both GCs and CCs is dependent on proper follicular angiogenesis. Aside from participating in complex molecular interplay with the oocyte, the ovarian follicular cells exhibit stem-like properties, characteristic of mesenchymal stem cells (MSCs). Both GCs and CCs remain under the influence of various miRNAs, and some of them may contribute to polycystic ovary syndrome (PCOS) or premature ovarian insufficiency (POI) occurrence. Considering increasing female fertility problems worldwide, it is of interest to develop new strategies enhancing assisted reproductive techniques. Therefore, it is important to carefully consider GCs as ovarian stem cells in terms of the cellular features and molecular pathways involved in their development and interactions as well as outline their possible application in translational medicine. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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33 pages, 1323 KiB

Open AccessReview

Towards Physiologic Culture Approaches to Improve Standard Cultivation of Mesenchymal Stem Cells

by Ilias Nikolits, Sabrina Nebel, Dominik Egger, Sebastian Kreß and Cornelia Kasper

Cells 2021, 10(4), 886; https://doi.org/10.3390/cells10040886 - 13 Apr 2021

Cited by 34 | Viewed by 5788

Abstract

Mesenchymal stem cells (MSCs) are of great interest for their use in cell-based therapies due to their multipotent differentiation and immunomodulatory capacities. In consequence of limited numbers following their isolation from the donor tissue, MSCs require extensive expansion performed in traditional 2D cell [...] Read more.

Mesenchymal stem cells (MSCs) are of great interest for their use in cell-based therapies due to their multipotent differentiation and immunomodulatory capacities. In consequence of limited numbers following their isolation from the donor tissue, MSCs require extensive expansion performed in traditional 2D cell culture setups to reach adequate amounts for therapeutic use. However, prolonged culture of MSCs in vitro has been shown to decrease their differentiation potential and alter their immunomodulatory properties. For that reason, preservation of these physiological characteristics of MSCs throughout their in vitro culture is essential for improving the efficiency of therapeutic and in vitro modeling applications. With this objective in mind, many studies already investigated certain parameters for enhancing current standard MSC culture protocols with regard to the effects of specific culture media components or culture conditions. Although there is a lot of diversity in the final therapeutic uses of the cells, the primary stage of standard isolation and expansion is imperative. Therefore, we want to review on approaches for optimizing standard MSC culture protocols during this essential primary step of in vitro expansion. The reviewed studies investigate and suggest improvements focused on culture media components (amino acids, ascorbic acid, glucose level, growth factors, lipids, platelet lysate, trace elements, serum, and xenogeneic components) as well as culture conditions and processes (hypoxia, cell seeding, and dissociation during passaging), in order to preserve the MSC phenotype and functionality during the primary phase of in vitro culture. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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22 pages, 4323 KiB

Open AccessReview

Trends in Articular Cartilage Tissue Engineering: 3D Mesenchymal Stem Cell Sheets as Candidates for Engineered Hyaline-Like Cartilage

by Hallie Thorp, Kyungsook Kim, Makoto Kondo, Travis Maak, David W. Grainger and Teruo Okano

Cells 2021, 10(3), 643; https://doi.org/10.3390/cells10030643 - 13 Mar 2021

Cited by 40 | Viewed by 6456

Abstract

Articular cartilage defects represent an inciting factor for future osteoarthritis (OA) and degenerative joint disease progression. Despite multiple clinically available therapies that succeed in providing short term pain reduction and restoration of limited mobility, current treatments do not reliably regenerate native hyaline cartilage [...] Read more.

Articular cartilage defects represent an inciting factor for future osteoarthritis (OA) and degenerative joint disease progression. Despite multiple clinically available therapies that succeed in providing short term pain reduction and restoration of limited mobility, current treatments do not reliably regenerate native hyaline cartilage or halt cartilage degeneration at these defect sites. Novel therapeutics aimed at addressing limitations of current clinical cartilage regeneration therapies increasingly focus on allogeneic cells, specifically mesenchymal stem cells (MSCs), as potent, banked, and available cell sources that express chondrogenic lineage commitment capabilities. Innovative tissue engineering approaches employing allogeneic MSCs aim to develop three-dimensional (3D), chondrogenically differentiated constructs for direct and immediate replacement of hyaline cartilage, improve local site tissue integration, and optimize treatment outcomes. Among emerging tissue engineering technologies, advancements in cell sheet tissue engineering offer promising capabilities for achieving both in vitro hyaline-like differentiation and effective transplantation, based on controlled 3D cellular interactions and retained cellular adhesion molecules. This review focuses on 3D MSC-based tissue engineering approaches for fabricating “ready-to-use” hyaline-like cartilage constructs for future rapid in vivo regenerative cartilage therapies. We highlight current approaches and future directions regarding development of MSC-derived cartilage therapies, emphasizing cell sheet tissue engineering, with specific focus on regulating 3D cellular interactions for controlled chondrogenic differentiation and post-differentiation transplantation capabilities. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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29 pages, 2154 KiB

Open AccessReview

The Future of Regenerative Medicine: Cell Therapy Using Pluripotent Stem Cells and Acellular Therapies Based on Extracellular Vesicles

by Margot Jarrige, Elie Frank, Elise Herardot, Sabrina Martineau, Annabelle Darle, Manon Benabides, Sophie Domingues, Olivier Chose, Walter Habeler, Judith Lorant, Christine Baldeschi, Cécile Martinat, Christelle Monville, Lise Morizur and Karim Ben M’Barek

Cells 2021, 10(2), 240; https://doi.org/10.3390/cells10020240 - 27 Jan 2021

Cited by 60 | Viewed by 13016

Abstract

The rapid progress in the field of stem cell research has laid strong foundations for their use in regenerative medicine applications of injured or diseased tissues. Growing evidences indicate that some observed therapeutic outcomes of stem cell-based therapy are due to paracrine effects [...] Read more.

The rapid progress in the field of stem cell research has laid strong foundations for their use in regenerative medicine applications of injured or diseased tissues. Growing evidences indicate that some observed therapeutic outcomes of stem cell-based therapy are due to paracrine effects rather than long-term engraftment and survival of transplanted cells. Given their ability to cross biological barriers and mediate intercellular information transfer of bioactive molecules, extracellular vesicles are being explored as potential cell-free therapeutic agents. In this review, we first discuss the state of the art of regenerative medicine and its current limitations and challenges, with particular attention on pluripotent stem cell-derived products to repair organs like the eye, heart, skeletal muscle and skin. We then focus on emerging beneficial roles of extracellular vesicles to alleviate these pathological conditions and address hurdles and operational issues of this acellular strategy. Finally, we discuss future directions and examine how careful integration of different approaches presented in this review could help to potentiate therapeutic results in preclinical models and their good manufacturing practice (GMP) implementation for future clinical trials. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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24 pages, 1135 KiB

Open AccessReview

Stem Cells and Extrusion 3D Printing for Hyaline Cartilage Engineering

by Océane Messaoudi, Christel Henrionnet, Kevin Bourge, Damien Loeuille, Pierre Gillet and Astrid Pinzano

Cells 2021, 10(1), 2; https://doi.org/10.3390/cells10010002 - 22 Dec 2020

Cited by 43 | Viewed by 5726

Abstract

Hyaline cartilage is deficient in self-healing properties. The early treatment of focal cartilage lesions is a public health challenge to prevent long-term degradation and the occurrence of osteoarthritis. Cartilage tissue engineering represents a promising alternative to the current insufficient surgical solutions. 3D printing [...] Read more.

Hyaline cartilage is deficient in self-healing properties. The early treatment of focal cartilage lesions is a public health challenge to prevent long-term degradation and the occurrence of osteoarthritis. Cartilage tissue engineering represents a promising alternative to the current insufficient surgical solutions. 3D printing is a thriving technology and offers new possibilities for personalized regenerative medicine. Extrusion-based processes permit the deposition of cell-seeded bioinks, in a layer-by-layer manner, allowing mimicry of the native zonal organization of hyaline cartilage. Mesenchymal stem cells (MSCs) are a promising cell source for cartilage tissue engineering. Originally isolated from bone marrow, they can now be derived from many different cell sources (e.g., synovium, dental pulp, Wharton’s jelly). Their proliferation and differentiation potential are well characterized, and they possess good chondrogenic potential, making them appropriate candidates for cartilage reconstruction. This review summarizes the different sources, origins, and densities of MSCs used in extrusion-based bioprinting (EBB) processes, as alternatives to chondrocytes. The different bioink constituents and their advantages for producing substitutes mimicking healthy hyaline cartilage is also discussed. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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9 pages, 3580 KiB

Open AccessPerspective

When the Search for Stemness Genes Meets the Skin Substitute Bioengineering Field: KLF4 Transcription Factor under the Light

by Nicolas O. Fortunel and Michèle T. Martin

Cells 2020, 9(10), 2188; https://doi.org/10.3390/cells9102188 - 28 Sep 2020

Cited by 4 | Viewed by 3448

Abstract

The transcription factor “Kruppel-like factor 4” (KLF4) is a central player in the field of pluripotent stem cell biology. In particular, it was put under the spotlight as one of the four factors of the cocktail originally described for reprogramming into induced pluripotent [...] Read more.

The transcription factor “Kruppel-like factor 4” (KLF4) is a central player in the field of pluripotent stem cell biology. In particular, it was put under the spotlight as one of the four factors of the cocktail originally described for reprogramming into induced pluripotent stem cells (iPSCs). In contrast, its possible functions in native tissue stem cells remain largely unexplored. We recently published that KLF4 is a regulator of “stemness” in human keratinocytes. We show that reducing the level of expression of this transcription factor by RNA interference or pharmacological repression promotes the ex vivo amplification and regenerative capacity of two types of cells of interest for cutaneous cell therapy: native keratinocyte stem and progenitor cells from adult epidermis, which have been used for more than three decades in skin graft bioengineering, and keratinocytes generated by the lineage-oriented differentiation of embryonic stem cells (ESCs), which have potential for the development of skin bio-bandages. At the mechanistic level, KLF4 repression alters the expression of a large set of genes involved in TGF-β1 and WNT signaling pathways. Major regulators of TGF-β bioavailability and different TGF-β receptors were targeted, notably modulating the ALK1/Smad1/5/9 axis. At a functional level, KLF4 repression produced an antagonist effect on TGF-β1-induced keratinocyte differentiation. Full article

(This article belongs to the Special Issue Feature Papers in Stem Cells)

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