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Mechanisms of Differentiation of Mesenchymal Stem Cells of Different Origin

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 28379

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Special Issue Editors

Dr. Anna B. Malashicheva

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Guest Editor

Laboratory of Regenerative Biomedicine, Institute of Cytology, Russian Academy of Sciences, Moscow, Russia
Interests: notch signaling; osteogenic differentiation; mesenchymal stem cells; endothelial-mesenchymal interactions

Dr. Natella Enukashvily

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Co-Guest Editor

Laboratory of the Non-Coding DNA Study, Institute of Cytology RAS, Saint Petersburg 194064, Russia
Interests: physiology of multipotent mesenchymal stromal cells and neural crest stem cells; non-coding RNA; genome architecture; endothelial-mesenchymal transition
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Special Issue Information

Dear Colleagues,

MSCs are actively studied from the point of view of both fundamental problems of cell differentiation and their practical application in biomedicine. The universal definition of MSC appeared in 2006 and has not changed much since then. MSCs are plastic-adherent cells capable of proliferation in vitro, having a certain set of surface antigens and capable of osteogenic, adipogenic, and chondrogenic differentiation. Obviously, many types of MSC-like cells fit such criteria. According to single-cell transcriptome analysis, even primary cultures of MSCs from one compartment are heterogeneous. This variability is superimposed on differences in cells between compartments. MSC-like cells are isolated from almost any tissue of mesenchymal origin, including bone, adipose, and muscle tissues, as well as heart, lungs, liver, blood, urine, etc. A significant role is played by the niche in which MSC-like cells are located in vivo. All this leads to the differential ability of different types of MSCs to proliferate and differentiate. We are faced with the question: is the phenomenologically similar process of this or that differentiation based on the same molecular mechanisms? Does differentiation occur in the same way in different types of MSCs in different compartments and does it lead to the formation of the same type of cells?

This Special Issue is devoted to the comparison of the mechanisms of differentiation of various types of MSC-like cells.

Dr. Anna B. Malashicheva
Guest Editor
Dr. Natella Enukashvily
Co-Guest Editor

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Keywords

mesenchymal stem cells
mechanisms of differentiation
major signaling activation

Published Papers (9 papers)

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Research

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18 pages, 3783 KiB

Open AccessArticle

Mesenchymal Stem Cells Isolated from Paediatric Paravertebral Adipose Tissue Show Strong Osteogenic Potential

by Jan Rožanc, Lidija Gradišnik, Tomaž Velnar, Minja Gregorič, Marko Milojević, Boštjan Vihar, Boris Gole and Uroš Maver

Biomedicines 2022, 10(2), 378; https://doi.org/10.3390/biomedicines10020378 - 4 Feb 2022

Cited by 8 | Viewed by 2109

Abstract

Mesenchymal stem cells (MSCs) represent the basis of novel clinical concepts in cellular therapy and tissue regeneration. Therefore, the isolation of MSCs from various tissues has become an important endeavour for stem cell biobanking and the development of regenerative therapies. Paravertebral adipose tissue is readily exposed during spinal procedures in children and could be a viable source of stem cells for therapeutic applications. Here, we describe the first case of MSCs isolated from paravertebral adipose tissue (PV-ADMSCs), obtained during a routine spinal surgery on a child. Using quantitative real-time PCR and flow cytometry, we show that PV-ADMSCs have different levels of stem marker expression compared to the MSCs from other sources while having the highest proliferation rate. Furthermore, we evaluate the multipotency of PV-ADMSCs by the three-lineage (adipogenic, osteogenic and chondrogenic) differentiation and compare it to the multipotency of MSCs from other sources. It was found that the PV-ADMSCs have a strong osteogenic potential in particular. Taken together, our data indicate that PV-ADMSCs meet the criteria for successful cell therapy, defined by the International Society for Cellular Therapy (ISCT), and thus, could provide a source of MSCs that is relatively easy to isolate and expand in culture. Due to their strong osteogenic potential, these cells provide a promising basis, especially for orthopaedic applications. Full article

(This article belongs to the Special Issue Mechanisms of Differentiation of Mesenchymal Stem Cells of Different Origin)

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19 pages, 3824 KiB

Open AccessArticle

Metformin Improves Stemness of Human Adipose-Derived Stem Cells by Downmodulation of Mechanistic Target of Rapamycin (mTOR) and Extracellular Signal-Regulated Kinase (ERK) Signaling

by Somaiah Chinnapaka, Katherine S. Yang, Quinn Flowers, Minhal Faisal, Wayne Vincent Nerone, Joseph Peter Rubin and Asim Ejaz

Biomedicines 2021, 9(12), 1782; https://doi.org/10.3390/biomedicines9121782 - 27 Nov 2021

Cited by 11 | Viewed by 2453

Abstract

Adipose tissue plays an important role in regulating metabolic homeostasis by storing excess fat and protecting other organs from lipotoxicity. Aging is associated with central fat redistribution, culminating in a decrease in insulin-sensitive subcutaneous and an increase in insulin-resistant visceral adipose depots. Adipose-derived stem cells (ASCs) play an important role in the regeneration of adipose tissue. Aged ASCs show decreased stemness and regenerative potential due to the accumulation of oxidative stress and mitochondrial dysfunction-related cell damage. Metformin is a well-established anti-diabetic drug that has shown anti-aging effects in different organisms and animal models. In this study, we analyzed the effect of metformin treatment on the stemness of human ASCs in cell culture and whole adipose tissue culture models. Our results demonstrate that metformin improves the stemness of ASCs, reducing their rate of proliferation and adipocyte differentiation. Investigating the possible underlying mechanism, we observed a decrease in the mTOR and ERK activity in metformin-treated ASCs. In addition, we observed an increase in autophagy activity upon metformin treatment. We conclude that metformin treatment improves ASCs stemness by reducing mTOR and ERK signaling and enhancing autophagy. Future in vivo evaluations in animal models and humans will pave the way for the clinical adaptation of this well-established drug for reviving the stemness of aged stem cells. Full article

(This article belongs to the Special Issue Mechanisms of Differentiation of Mesenchymal Stem Cells of Different Origin)

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26 pages, 3671 KiB

Open AccessArticle

Comparative Analysis of Dental Pulp and Periodontal Stem Cells: Differences in Morphology, Functionality, Osteogenic Differentiation and Proteome

by Anastasia V. Kotova, Arseniy A. Lobov, Julia A. Dombrovskaya, Valentina Y. Sannikova, Nadezhda A. Ryumina, Polina Klausen, Alexey L. Shavarda, Anna B. Malashicheva and Natella I. Enukashvily

Biomedicines 2021, 9(11), 1606; https://doi.org/10.3390/biomedicines9111606 - 3 Nov 2021

Cited by 18 | Viewed by 4241

Abstract

Dental stem cells are heterogeneous in their properties. Despite their common origin from neural crest stem cells, they have different functional capacities and biological functions due to niche influence. In this study, we assessed the differences between dental pulp stem cells (DPSC) and periodontal ligament stem cells (PDLSC) in their pluripotency and neuroepithelial markers transcription, morphological and functional features, osteoblast/odontoblast differentiation and proteomic profile during osteogenic differentiation. The data were collected in paired observations: two cell cultures, DPSC and PDLSC, were obtained from each donor. Both populations had the mesenchymal stem cells surface marker set exposed on their membranes but differed in Nestin (a marker of neuroectodermal origin) expression, morphology, and proliferation rate. OCT4 mRNA was revealed in DPSC and PDLSC, while OCT4 protein was present in the nuclei of DPSC only. However, transcription of OCT4 mRNA was 1000–10,000-fold lower in dental stem cells than in blastocysts. DPSC proliferated at a slower rate and have a shape closer to polygonal but they responded better to osteogenic stimuli as compared to PDLSC. RUNX2 mRNA was detected by qPCR in both types of dental stem cells but RUNX2 protein was detected by LC-MS/MS shotgun proteomics only in PDLSC suggesting the posttranscriptional regulation. DSPP and DMP1, marker genes of odontoblastic type of osteogenic differentiation, were transcribed in DPSC but not in PDLSC samples. Our results prove that DPSC and PDLSC are different in their biology and therapeutic potential: DPSC are a good candidate for osteogenic or odontogenic bone-replacement cell-seeded medicines, while fast proliferating PDLSC are a prospective candidate for other cell products. Full article

(This article belongs to the Special Issue Mechanisms of Differentiation of Mesenchymal Stem Cells of Different Origin)

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16 pages, 3247 KiB

Open AccessArticle

Targeting Brain Tumors with Mesenchymal Stem Cells in the Experimental Model of the Orthotopic Glioblastoma in Rats

by Natalia Yudintceva, Ekaterina Lomert, Natalia Mikhailova, Elena Tolkunova, Nikol Agadzhanian, Konstantin Samochernych, Gabriele Multhoff, Grigoriy Timin, Vyacheslav Ryzhov, Vladimir Deriglazov, Anton Mazur and Maxim Shevtsov

Biomedicines 2021, 9(11), 1592; https://doi.org/10.3390/biomedicines9111592 - 1 Nov 2021

Cited by 6 | Viewed by 3014

Abstract

Despite multimodal approaches for the treatment of multiforme glioblastoma (GBM) advances in outcome have been very modest indicating the necessity of novel diagnostic and therapeutic strategies. Currently, mesenchymal stem cells (MSCs) represent a promising platform for cell-based cancer therapies because of their tumor-tropism, low immunogenicity, easy accessibility, isolation procedure, and culturing. In the present study, we assessed the tumor-tropism and biodistribution of the superparamagnetic iron oxide nanoparticle (SPION)-labeled MSCs in the orthotopic model of C6 glioblastoma in Wistar rats. As shown in in vitro studies employing confocal microscopy, high-content quantitative image cytometer, and xCelligence system MSCs exhibit a high migratory capacity towards C6 glioblastoma cells. Intravenous administration of SPION-labeled MSCs in vivo resulted in intratumoral accumulation of the tagged cells in the tumor tissues that in turn significantly enhanced the contrast of the tumor when high-field magnetic resonance imaging was performed. Subsequent biodistribution studies employing highly sensitive nonlinear magnetic response measurements (NLR-M₂) supported by histological analysis confirm the retention of MSCs in the glioblastoma. In conclusion, MSCs due to their tumor-tropism could be employed as a drug-delivery platform for future theranostic approaches. Full article

(This article belongs to the Special Issue Mechanisms of Differentiation of Mesenchymal Stem Cells of Different Origin)

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35 pages, 8960 KiB

Open AccessArticle

Self-Organization Provides Cell Fate Commitment in MSC Sheet Condensed Areas via ROCK-Dependent Mechanism

by Peter Nimiritsky, Ekaterina Novoseletskaya, Roman Eremichev, Natalia Alexandrushkina, Maxim Karagyaur, Oleg Vetrovoy, Nataliya Basalova, Anastasia Khrustaleva, Alexander Tyakht, Anastasia Efimenko, Vsevolod Tkachuk and Pavel Makarevich

Biomedicines 2021, 9(9), 1192; https://doi.org/10.3390/biomedicines9091192 - 10 Sep 2021

Cited by 6 | Viewed by 3790

Abstract

Multipotent mesenchymal stem/stromal cells (MSC) are one of the crucial regulators of regeneration and tissue repair and possess an intrinsic program from self-organization mediated by condensation, migration and self-patterning. The ability to self-organize has been successfully exploited in tissue engineering approaches using cell sheets (CS) and their modifications. In this study, we used CS as a model of human MSC spontaneous self-organization to demonstrate its structural, transcriptomic impact and multipotent stromal cell commitment. We used CS formation to visualize MSC self-organization and evaluated the role of the Rho-GTPase pathway in spontaneous condensation, resulting in a significant anisotropy of the cell density within the construct. Differentiation assays were carried out using conventional protocols, and microdissection and RNA-sequencing were applied to establish putative targets behind the observed phenomena. The differentiation of MSC to bone and cartilage, but not to adipocytes in CS, occurred more effectively than in the monolayer. RNA-sequencing indicated transcriptional shifts involving the activation of the Rho-GTPase pathway and repression of SREBP, which was concordant with the lack of adipogenesis in CS. Eventually, we used an inhibitory analysis to validate our findings and suggested a model where the self-organization of MSC defined their commitment and cell fate via ROCK1/2 and SREBP as major effectors under the putative switching control of AMP kinase. Full article

(This article belongs to the Special Issue Mechanisms of Differentiation of Mesenchymal Stem Cells of Different Origin)

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17 pages, 7843 KiB

Open AccessArticle

Derivation and Characterization of EGFP-Labeled Rabbit Limbal Mesenchymal Stem Cells and Their Potential for Research in Regenerative Ophthalmology

by Julia I. Khorolskaya, Daria A. Perepletchikova, Daniel V. Kachkin, Kirill E. Zhurenkov, Elga I. Alexander-Sinkler, Julia S. Ivanova, Natalia A. Mikhailova and Miralda I. Blinova

Biomedicines 2021, 9(9), 1134; https://doi.org/10.3390/biomedicines9091134 - 1 Sep 2021

Cited by 5 | Viewed by 2600

Abstract

The development of cell-based approaches to the treatment of various cornea pathologies, including limbal stem cell deficiency (LSCD), is an area of current interest in regenerative biomedicine. In this context, the shortage of donor material is urgent, and limbal mesenchymal stem cells (L-MSCs) may become a promising cell source for the development of these novel approaches, being established mainly within the rabbit model. In this study, we obtained and characterized rabbit L-MSCs and modified them with lentiviral transduction to express the green fluorescent protein EGFP (L-MSCs-EGFP). L-MSCs and L-MSCs-EGFP express not only stem cell markers specific for mesenchymal stem cells but also ABCG2, ABCB5, ALDH3A1, PAX6, and p63a specific for limbal epithelial stem cells (LESCs), as well as various cytokeratins (3/12, 15, 19). L-MSCs-EGFP have been proven to differentiate into adipogenic, osteogenic, and chondrogenic directions, as well as to transdifferentiate into epithelial cells. The possibility of using L-MSCs-EGFP to study the biocompatibility of various scaffolds developed to treat corneal pathologies was demonstrated. L-MSCs-EGFP may become a useful tool for studying regenerative processes occurring during the treatment of various corneal pathologies, including LSCD, with the use of cell-based technologies. Full article

(This article belongs to the Special Issue Mechanisms of Differentiation of Mesenchymal Stem Cells of Different Origin)

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12 pages, 2545 KiB

Open AccessArticle

Context-Specific Osteogenic Potential of Mesenchymal Stem Cells

by Aleksandra Kostina, Arseniy Lobov, Daria Semenova, Artem Kiselev, Polina Klausen and Anna Malashicheva

Biomedicines 2021, 9(6), 673; https://doi.org/10.3390/biomedicines9060673 - 12 Jun 2021

Cited by 7 | Viewed by 2662

Abstract

Despite the great progress in the field of bone tissue regeneration, the early initiating mechanisms of osteogenic differentiation are not well understood. Cells capable of osteogenic transformation vary from mesenchymal stem cells of various origins to mural cells of vessels. The mechanisms of pathological calcification are thought to be similar to those of bone formation. Notch signaling has been shown to play an important role in osteogenic differentiation, as well as in pathological calcification. Nevertheless, despite its known tissue- and context-specificity, the information about its role in the osteogenic differentiation of different cells is still limited. We compared mesenchymal stem cells from adipogenic tissue (MSCs) and interstitial cells from the aortic valve (VICs) by their ability to undergo Notch-dependent osteogenic differentiation. We showed differences between the two types of cells in their ability to activate the expression of proosteogenic genes RUNX2, BMP2, BMP4, DLX2, BGLAP, SPRY, IBSP, and SPP1 in response to Notch activation. Untargeted metabolomic profiling also confirms differences between MSCs and VICs in their osteogenic state. Analysis of the activity of RUNX2 and SPP1 promoters shows fine-tuned dose-dependency in response to Notch induction and suggests a direct link between the level of Notch activation, and the proostogenic gene expression and corresponding osteogenic induction. Our data suggest that osteogenic differentiation is a context-dependent process and the outcome of it could be cell-type dependent. Full article

(This article belongs to the Special Issue Mechanisms of Differentiation of Mesenchymal Stem Cells of Different Origin)

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Review

Jump to: Research

28 pages, 1369 KiB

Open AccessReview

Methods of Modification of Mesenchymal Stem Cells and Conditions of Their Culturing for Hyaline Cartilage Tissue Engineering

by Maria V. Shestovskaya, Svetlana A. Bozhkova, Julia V. Sopova, Mikhail G. Khotin and Mikhail S. Bozhokin

Biomedicines 2021, 9(11), 1666; https://doi.org/10.3390/biomedicines9111666 - 11 Nov 2021

Cited by 6 | Viewed by 3000

Abstract

The use of mesenchymal stromal cells (MSCs) for tissue engineering of hyaline cartilage is a topical area of regenerative medicine that has already entered clinical practice. The key stage of this procedure is to create conditions for chondrogenic differentiation of MSCs, increase the synthesis of hyaline cartilage extracellular matrix proteins by these cells and activate their proliferation. The first such works consisted in the indirect modification of cells, namely, in changing the conditions in which they are located, including microfracturing of the subchondral bone and the use of 3D biodegradable scaffolds. The most effective methods for modifying the cell culture of MSCs are protein and physical, which have already been partially introduced into clinical practice. Genetic methods for modifying MSCs, despite their effectiveness, have significant limitations. Techniques have not yet been developed that allow studying the effectiveness of their application even in limited groups of patients. The use of MSC modification methods allows precise regulation of cell culture proliferation, and in combination with the use of a 3D biodegradable scaffold, it allows obtaining a hyaline-like regenerate in the damaged area. This review is devoted to the consideration and comparison of various methods used to modify the cell culture of MSCs for their use in regenerative medicine of cartilage tissue. Full article

(This article belongs to the Special Issue Mechanisms of Differentiation of Mesenchymal Stem Cells of Different Origin)

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15 pages, 1032 KiB

Open AccessReview

Autophagy, Mesenchymal Stem Cell Differentiation, and Secretion

by Mikhail Menshikov, Ekaterina Zubkova, Iuri Stafeev and Yelena Parfyonova

Biomedicines 2021, 9(9), 1178; https://doi.org/10.3390/biomedicines9091178 - 7 Sep 2021

Cited by 12 | Viewed by 3059

Abstract

Mesenchymal stem cells (MSC) are multipotent cells capable to differentiate into adipogenic, osteogenic, and chondrogenic directions, possessing immunomodulatory activity and a capability to stimulate angiogenesis. A scope of these features and capabilities makes MSC a significant factor of tissue homeostasis and repair. Among factors determining the fate of MSC, a prominent place belongs to autophagy, which is activated under different conditions including cell starvation, inflammation, oxidative stress, and some others. In addition to supporting cell homeostasis by elimination of protein aggregates, and non-functional and damaged proteins, autophagy is a necessary factor of change in cell phenotype on the process of cell differentiation. In present review, some mechanisms providing participation of autophagy in cell differentiation are discussed Full article

(This article belongs to the Special Issue Mechanisms of Differentiation of Mesenchymal Stem Cells of Different Origin)

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