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

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 21571

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Dr. Mirko Manetti

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Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, 50134 Florence, Italy
Interests: anatomy; histology; morphological and functional aspects of stromal cells; endothelial cell biology; angiogenesis; cellular and molecular mechanisms of tissue fibrosis; pathogenesis of autoimmune, chronic inflammatory and connective tissue diseases; animal models of human disorders.
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Dear Colleagues,

I am very glad to announce a Special Issue entitled "Molecular Morphology and Function of Stromal Cells" that is being prepared for the International Journal of Molecular Sciences.

The term “stromal cells” refers to a highly heterogeneous class of connective tissue cells that build the infrastructure of any organ and fulfill a variety of fundamental roles in health and disease. Embedded into the framework of stromal cells are parenchymal cells, which define the specific function of an organ. Distinctive populations of stromal cells with different morphologies and functions include i) fibroblasts, pericytes, and telocytes that are widely distributed throughout various organ systems, ii) cells with stemness features such as mesenchymal stem/stromal cells and adipose-tissue-derived stem/stromal cells, and iii) stromal cells specifically restricted to some organs, as interstitial cells of Cajal in the gastrointestinal tract muscularis and fibroblastic reticular cells in secondary lymphoid organs, among others.

In recent years, there have been substantial advances in our understanding of stromal cell biology, especially the molecular signals underlying their contribution to several biological processes in different tissues, including tissue morphogenesis and development, maintenance of local tissue homeostasis, tissue injury, regeneration, immune responses, cancer, and other pathologies. Increasing evidence indeed indicates that stromal cells are leading actors in shaping the organization, integrity, and dynamics of their own microenvironment, but their phenotype and functions also are tightly dependent on the specific tissue microenvironment where they reside.

Expanding our knowledge of the cellular and molecular mechanisms regulating the interactions of stromal cells among themselves and with neighbor parenchymal cells or tissue-resident stem cells in physiological and pathophysiological contexts is crucial to gain insights into their potential clinical relevance as therapeutic targets or tools in the translational field of tissue engineering and regenerative medicine.

Outstanding experts interested in this Special Issue are very welcome to submit original manuscripts and reviews dealing with any of the abovementioned aspects of stromal cell biology.

Dr. Mirko Manetti
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.

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Keywords

stromal cells
fibroblasts
telocytes
pericytes
mesenchymal stem/stromal cells
adipose tissue-derived stem/stromal cells
intercellular communication
molecular signaling
tissue homeostasis
therapeutic targets
tissue engineering
regenerative medicine

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Related Special Issue

Molecular Morphology and Function of Stromal Cells in International Journal of Molecular Sciences (10 articles)

Published Papers (8 papers)

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Editorial

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4 pages, 185 KiB

Open AccessEditorial

Molecular Morphology and Function of Stromal Cells

by Mirko Manetti

Int. J. Mol. Sci. 2021, 22(24), 13422; https://doi.org/10.3390/ijms222413422 - 14 Dec 2021

Cited by 12 | Viewed by 2944

Abstract

(This article belongs to the Special Issue Molecular Morphology and Function of Stromal Cells 2.0)

Research

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16 pages, 5357 KiB

Open AccessArticle

Tri-Lineage Differentiation Potential of Osteosarcoma Cell Lines and Human Bone Marrow Stromal Cells from Different Anatomical Locations

by Hannah L. Smith, Juliet C. Gray, Stephen A. Beers and Janos M. Kanczler

Int. J. Mol. Sci. 2023, 24(4), 3667; https://doi.org/10.3390/ijms24043667 - 11 Feb 2023

Cited by 2 | Viewed by 2570

Abstract

The bone cancer osteosarcoma, found mainly in adolescents, routinely forms around the growth plate/metaphysis of long bones. Bone marrow composition changes with age, shifting from a more hematopoietic to an adipocyte-rich tissue. This conversion occurs in the metaphysis during adolescence, implicating a link between bone marrow conversion and osteosarcoma initiation. To assess this, the tri-lineage differentiation potential of human bone marrow stromal cells (HBMSCs) isolated from the femoral diaphysis/metaphysis (FD) and epiphysis (FE) was characterized and compared to two osteosarcoma cell lines, Saos-2 and MG63. Compared to FE-cells, FD-cells showed an increase in tri-lineage differentiation. Additionally, differences were found between the Saos-2 cells exhibiting higher levels of osteogenic differentiation, lower adipogenic differentiation, and a more developed chondrogenic phenotype than MG63, with the Saos-2 being more comparable to FD-derived HBMSCs. The differences found between the FD and FE derived cells are consistent with the FD region containing more hematopoietic tissue compared to the FE. This may be related to the similarities between FD-derived cells and Saos-2 cells during osteogenic and chondrogenic differentiation. These studies reveal distinct differences in the tri-lineage differentiations of ‘hematopoietic’ and ‘adipocyte rich’ bone marrow, which correlate with specific characteristics of the two osteosarcoma cell lines. Full article

(This article belongs to the Special Issue Molecular Morphology and Function of Stromal Cells 2.0)

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18 pages, 3906 KiB

Open AccessArticle

The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Attenuates Transforming Growth Factor β1-Induced Myofibroblast Differentiation of Human Corneal Keratocytes

by Irene Rosa, Bianca Saveria Fioretto, Eloisa Romano, Matilde Buzzi, Rita Mencucci, Mirca Marini and Mirko Manetti

Int. J. Mol. Sci. 2022, 23(23), 15325; https://doi.org/10.3390/ijms232315325 - 5 Dec 2022

Cited by 4 | Viewed by 1932

Abstract

Corneal transparency, necessary for vision and depending on the high organization of stromal extracellular matrix, is maintained by keratocytes. Severe or continuous corneal injuries determine exaggerated healing responses resulting in the formation of irreversible fibrotic scars and vision impairment. Soluble guanylate cyclase (sGC) stimulation demonstrated antifibrotic effects in both experimental fibrosis and human lung and skin fibroblasts. Here, we assessed whether sGC stimulation with BAY 41-2272 could attenuate transforming growth factor β1 (TGFβ1)-induced myofibroblast differentiation of human corneal keratocytes. Cells were challenged with TGFβ1, with/without BAY 41-2272 preincubation, and subsequently assessed for viability, proliferation, migration, chemoinvasion, as well for the expression of myofibroblast/fibroblast activation markers and contractile abilities. Treatment with BAY 41-2272 did not affect keratocyte viability, while preincubation of cells with the sGC stimulator was able to inhibit TGFβ1-induced proliferation, wound healing capacity, and invasiveness. BAY 41-2272 was also able to attenuate TGFβ1-induced myofibroblast-like profibrotic phenotype of keratocytes, as demonstrated by the significant decrease in ACTA2, COL1A1, COL1A2, FN1 and PDPN gene expression, as well as in α-smooth muscle actin, α-1 chain of type I collagen, podoplanin, vimentin and N-cadherin protein expression. Finally, BAY 41-2272 significantly counteracted the TGFβ1-induced myofibroblast-like ability of keratocytes to contract collagen gels, reduced phosphorylated Smad3 protein levels, and attenuated gene expression of proinflammatory cytokines. Collectively, our data show for the first time that BAY 41-2272 is effective in counteracting keratocyte-to-myofibroblast transition, thus providing the rationale for the development of sGC stimulators as novel promising modulators of corneal scarring and fibrosis. Full article

(This article belongs to the Special Issue Molecular Morphology and Function of Stromal Cells 2.0)

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12 pages, 2188 KiB

Open AccessArticle

Cryobanking European Mink (Mustela lutreola) Mesenchymal Stem Cells and Oocytes

by Alexandra Calle and Miguel Ángel Ramírez

Int. J. Mol. Sci. 2022, 23(16), 9319; https://doi.org/10.3390/ijms23169319 - 18 Aug 2022

Cited by 2 | Viewed by 2197

Abstract

The European mink (Mustela lutreola) is one of Europe’s most endangered species, and it is on the brink of extinction in the Iberian Peninsula. The species’ precarious situation requires the application of new ex situ conservation methodologies that complement the existing ex situ and in situ conservation measures. Here, we report for the first time the establishment of a biobank for European mink mesenchymal stem cells (emMSC) and oocytes from specimens found dead in the Iberian Peninsula, either free or in captivity. New emMSC lines were isolated from different tissues: bone marrow (emBM-MSC), oral mucosa (emOM-MSc), dermal skin (emDS-MSC), oviduct (emO-MSc), endometrium (emE-MSC), testicular (emT-MSC), and adipose tissue from two different adipose depots: subcutaneous (emSCA-MSC) and ovarian (emOA-MSC). All eight emMSC lines showed plastic adhesion, a detectable expression of characteristic markers of MSCs, and, when cultured under osteogenic and adipogenic conditions, differentiation capacity to these lineages. Additionally, we were able to keep 227 Cumulus-oocyte complexes (COCs) in the biobank, 97 of which are grade I or II. The European mink MSC and oocyte biobank will allow for the conservation of the species’ genetic variability, the application of assisted reproduction techniques, and the development of in vitro models for studying the molecular mechanisms of infectious diseases that threaten the species’ precarious situation. Full article

(This article belongs to the Special Issue Molecular Morphology and Function of Stromal Cells 2.0)

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11 pages, 3794 KiB

Open AccessArticle

Comparison of Biological Features of Wild European Rabbit Mesenchymal Stem Cells Derived from Different Tissues

by Alexandra Calle, María Zamora-Ceballos, Juan Bárcena, Esther Blanco and Miguel Ángel Ramírez

Int. J. Mol. Sci. 2022, 23(12), 6420; https://doi.org/10.3390/ijms23126420 - 8 Jun 2022

Cited by 4 | Viewed by 2499

Abstract

Although the European rabbit is an “endangered” species and a notorious biological model, the analysis and comparative characterization of new tissue sources of rabbit mesenchymal stem cells (rMSCs) have not been well addressed. Here, we report for the first time the isolation and characterization of rMSCs derived from an animal belonging to a natural rabbit population within the native region of the species. New rMSC lines were isolated from different tissues: oral mucosa (rOM-MSC), dermal skin (rDS-MSC), subcutaneous adipose tissue (rSCA-MSC), ovarian adipose tissue (rOA-MSC), oviduct (rO-MSC), and mammary gland (rMG-MSC). The six rMSC lines showed plastic adhesion with fibroblast-like morphology and were all shown to be positive for CD44 and CD29 expression (characteristic markers of MSCs), and negative for CD34 or CD45 expression. In terms of pluripotency features, all rMSC lines expressed NANOG, OCT4, and SOX2. Furthermore, all rMSC lines cultured under osteogenic, chondrogenic, and adipogenic conditions showed differentiation capacity. In conclusion, this study describes the isolation and characterization of new rabbit cell lines from different tissue origins, with a clear mesenchymal pattern. We show that rMSC do not exhibit differences in terms of morphological features, expression of the cell surface, and intracellular markers of pluripotency and in vitro differentiation capacities, attributable to their tissue of origin. Full article

(This article belongs to the Special Issue Molecular Morphology and Function of Stromal Cells 2.0)

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22 pages, 3691 KiB

Open AccessArticle

Mesenchymal Stromal Cells from Healthy and Inflamed Human Gingiva Respond Differently to Porphyromonas gingivalis

by Marina Bekić, Marina Radanović, Jelena Đokić, Sergej Tomić, Mile Eraković, Dušan Radojević, Miloš Duka, Dejan Marković, Milan Marković, Bashkim Ismaili, Dejan Bokonjić and Miodrag Čolić

Int. J. Mol. Sci. 2022, 23(7), 3510; https://doi.org/10.3390/ijms23073510 - 23 Mar 2022

Cited by 6 | Viewed by 2964

Abstract

Gingiva-Derived Mesenchymal Stromal Cells (GMSCs) have been shown to play an important role in periodontitis. However, how P. gingivalis, one of the key etiological agents of the disease, affects healthy (H)- and periodontitis (P)-GMSCs is unknown. To address this problem, we established 10 H-GMSC and 12 P-GMSC lines. No significant differences in morphology, differentiation into chondroblasts and adipocytes, expression of characteristic MSCS markers, including pericyte antigens NG2 and PDGFR, were observed between H- and P-GMSC lines. However, proliferation, cell size and osteogenic potential were higher in P-GMSCs, in contrast to their lower ability to suppress mononuclear cell proliferation. P. gingivalis up-regulated the mRNA expression of IL-6, IL-8, MCP-1, GRO-α, RANTES, TLR-2, HIF-1α, OPG, MMP-3, SDF-1, HGF and IP-10 in P-GMSCs, whereas only IL-6, MCP-1 and GRO-α were up-regulated in H-GMSCs. The expression of MCP-1, RANTES, IP-10 and HGF was significantly higher in P-GMSCs compared to H-GMSCs, but IDO1 was lower. No significant changes in the expression of TLR-3, TLR-4, TGF-β, LAP, IGFBP4 and TIMP-1 were observed in both types of GMSCs. In conclusion, our results suggest that P-GMSCs retain their pro-inflammatory properties in culture, exhibit lower immunosuppressive potential than their healthy counterparts, and impaired regeneration-associated gene induction in culture. All these functions are potentiated significantly by P. gingivalis treatment. Full article

(This article belongs to the Special Issue Molecular Morphology and Function of Stromal Cells 2.0)

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17 pages, 1457 KiB

Open AccessArticle

An Evaluation of Different 3D Cultivation Models on Expression Profiles of Human Periodontal Ligament Fibroblasts with Compressive Strain

by Agnes Schröder, Ricarda Schöniger, Juliane Oeldemann, Gerrit Spanier, Peter Proff, Jonathan Jantsch, Christian Kirschneck and Niklas Ullrich

Int. J. Mol. Sci. 2022, 23(4), 2029; https://doi.org/10.3390/ijms23042029 - 12 Feb 2022

Cited by 7 | Viewed by 2308

Abstract

The effects of compressive strain during orthodontic treatment on gene expression profiles of periodontal ligament fibroblasts (PDLFs) have mostly been studied in 2D cell culture. However, cells behave differently in many aspects in 3D culture. Therefore, the effect of pressure application on PDLFs in different 3D structures was investigated. PDLFs were either conventionally seeded or embedded into different 3D structures (spheroids, Mebiol^® gel, 3D scaffolds) and exposed to compressive force or incubated without pressure. For one 3D scaffold (POR), we also tested the effect of different compressive forces and application times. Expression of an angiogenic gene (VEGF), a gene involved in extracellular matrix synthesis (COL1A2), inflammatory genes (IL6, PTGS2), and genes involved in bone remodelling (OPG, RANKL) were investigated by RT–qPCR. Depending on the used 3D cell culture model, we detected different effects of compressive strain on expression profiles of PDLFs. COL1A2 was downregulated in all investigated 3D culture models. Angiogenetic and proinflammatory genes were regulated differentially between models. In 3D scaffolds, regulation of bone-remodelling genes upon compressive force was contrary to that observed in 3D gels. 3D cell culture models provide better approximations to in vivo physiology, compared with conventional 2D models. However, it is crucial which 3D structures are used, as these showed diverse effects on the expression profiles of PDLFs during mechanical strain. Full article

(This article belongs to the Special Issue Molecular Morphology and Function of Stromal Cells 2.0)

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Review

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31 pages, 10813 KiB

Open AccessReview

Comparison of the Behavior of Perivascular Cells (Pericytes and CD34+ Stromal Cell/Telocytes) in Sprouting and Intussusceptive Angiogenesis

by Lucio Díaz-Flores, Ricardo Gutiérrez, Maria Pino García, Miriam González-Gómez, Lucio Díaz-Flores, Jr., Jose Luis Carrasco, Juan Francisco Madrid and Aixa Rodríguez Bello

Int. J. Mol. Sci. 2022, 23(16), 9010; https://doi.org/10.3390/ijms23169010 - 12 Aug 2022

Cited by 11 | Viewed by 3080

Abstract

Perivascular cells in the pericytic microvasculature, pericytes and CD34+ stromal cells/telocytes (CD34+SCs/TCs), have an important role in angiogenesis. We compare the behavior of these cells depending on whether the growth of endothelial cells (ECs) from the pre-existing microvasculature is toward the interstitium with vascular bud and neovessel formation (sprouting angiogenesis) or toward the vascular lumen with intravascular pillar development and vessel division (intussusceptive angiogenesis). Detachment from the vascular wall, mobilization, proliferation, recruitment, and differentiation of pericytes and CD34+SCs/TCs, as well as associated changes in vessel permeability and functionality, and modifications of the extracellular matrix are more intense, longer lasting over time, and with a greater energy cost in sprouting angiogenesis than in intussusceptive angiogenesis, in which some of the aforementioned events do not occur or are compensated for by others (e.g., sparse EC and pericyte proliferation by cell elongation and thinning). The governing mechanisms involve cell–cell contacts (e.g., peg-and-socket junctions between pericytes and ECs), multiple autocrine and paracrine signaling molecules and pathways (e.g., vascular endothelial growth factor, platelet-derived growth factor, angiopoietins, transforming growth factor B, ephrins, semaphorins, and metalloproteinases), and other factors (e.g., hypoxia, vascular patency, and blood flow). Pericytes participate in vessel development, stabilization, maturation and regression in sprouting angiogenesis, and in interstitial tissue structure formation of the pillar core in intussusceptive angiogenesis. In sprouting angiogenesis, proliferating perivascular CD34+SCs/TCs are an important source of stromal cells during repair through granulation tissue formation and of cancer-associated fibroblasts (CAFs) in tumors. Conversely, CD34+SCs/TCs have less participation as precursor cells in intussusceptive angiogenesis. The dysfunction of these mechanisms is involved in several diseases, including neoplasms, with therapeutic implications. Full article

(This article belongs to the Special Issue Molecular Morphology and Function of Stromal Cells 2.0)

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