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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 October 2021) | Viewed by 39105

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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 2.0 in International Journal of Molecular Sciences (8 articles)

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Research

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15 pages, 10759 KiB

Open AccessArticle

Adipose Tissue-Derived Stromal Cells Alter the Mechanical Stability and Viscoelastic Properties of Gelatine Methacryloyl Hydrogels

by Francisco Drusso Martinez-Garcia, Martine Margaretha Valk, Prashant Kumar Sharma, Janette Kay Burgess and Martin Conrad Harmsen

Int. J. Mol. Sci. 2021, 22(18), 10153; https://doi.org/10.3390/ijms221810153 - 21 Sep 2021

Cited by 18 | Viewed by 3248

Abstract

The extracellular matrix provides mechanical cues to cells within it, not just in terms of stiffness (elasticity) but also time-dependent responses to deformation (viscoelasticity). In this work, we determined the viscoelastic transformation of gelatine methacryloyl (GelMA) hydrogels caused by adipose tissue-derived stromal cells (ASCs) through mathematical modelling. GelMA-ASCs combination is of interest to model stem cell-driven repair and to understand cell-biomaterial interactions in 3D environments. Immortalised human ASCs were embedded in 5%, 10%, and 15% (w/v) GelMA hydrogels and evaluated for 14 d. GelMA had a concentration-dependent increase in stiffness, but cells decreased this stiffness over time, across concentrations. Viscoelastic changes in terms of stress relaxation increased progressively in 5% GelMA, while mathematical Maxwell analysis showed that the relative importance (R_i) of the fastest Maxwell elements increased proportionally. The 10% GelMA only showed differences at 7 d. In contrast, ASCs in 15% GelMA caused slower stress relaxation, increasing the R_i of the slowest Maxwell element. We conclude that GelMA concentration influenced the stiffness and number of Maxwell elements. ASCs changed the percentage stress relaxation and R_i of Maxwell elements transforming hydrogel viscoelasticity into a more fluid environment over time. Overall, 5% GelMA induced the most favourable ASC response. Full article

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

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11 pages, 2560 KiB

Open AccessArticle

Aquatic Training after Joint Immobilization in Rats Promotes Adaptations in Myotendinous Junctions

by Lara Caetano Rocha, Gabriela Klein Barbosa, Jurandyr Pimentel Neto, Carolina dos Santos Jacob, Andreas B. Knudsen, Ii-Sei Watanabe and Adriano Polican Ciena

Int. J. Mol. Sci. 2021, 22(13), 6983; https://doi.org/10.3390/ijms22136983 - 29 Jun 2021

Cited by 6 | Viewed by 2587

Abstract

The myotendinous junction (MTJ) is the muscle-tendon interface and constitutes an integrated mechanical unit to force transmission. Joint immobilization promotes muscle atrophy via disuse, while physical exercise can be used as an adaptative stimulus. In this study, we aimed to investigate the components of the MTJ and their adaptations and the associated elements triggered with aquatic training after joint immobilization. Forty-four male Wistar rats were divided into sedentary (SD), aquatic training (AT), immobilization (IM), and immobilization/aquatic training (IMAT) groups. The samples were processed to measure fiber area, nuclear fractal dimension, MTJ nuclear density, identification of telocytes, sarcomeres, and MTJ perimeter length. In the AT group, the maintenance of ultrastructure and elements in the MTJ region were observed; the IM group presented muscle atrophy effects with reduced MTJ perimeter; the IMAT group demonstrated that aquatic training after joint immobilization promotes benefits in the muscle fiber area and fractal dimension, in the MTJ region shows longer sarcomeres and MTJ perimeter. We identified the presence of telocytes in the MTJ region in all experimental groups. We concluded that aquatic training is an effective rehabilitation method after joint immobilization due to reduced muscle atrophy and regeneration effects on MTJ in rats. Full article

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

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21 pages, 3321 KiB

Open AccessArticle

Proteomic Comparison of Bone Marrow Derived Osteoblasts and Mesenchymal Stem Cells

by Elise Aasebø, Annette K. Brenner, Maria Hernandez-Valladares, Even Birkeland, Frode S. Berven, Frode Selheim and Øystein Bruserud

Int. J. Mol. Sci. 2021, 22(11), 5665; https://doi.org/10.3390/ijms22115665 - 26 May 2021

Cited by 17 | Viewed by 5869

Abstract

Mesenchymal stem cells (MSCs) can differentiate into osteoblasts, and therapeutic targeting of these cells is considered both for malignant and non-malignant diseases. We analyzed global proteomic profiles for osteoblasts derived from ten and MSCs from six healthy individuals, and we quantified 5465 proteins for the osteoblasts and 5420 proteins for the MSCs. There was a large overlap in the profiles for the two cell types; 156 proteins were quantified only in osteoblasts and 111 proteins only for the MSCs. The osteoblast-specific proteins included several extracellular matrix proteins and a network including 27 proteins that influence intracellular signaling (Wnt/Notch/Bone morphogenic protein pathways) and bone mineralization. The osteoblasts and MSCs showed only minor age- and sex-dependent proteomic differences. Finally, the osteoblast and MSC proteomic profiles were altered by ex vivo culture in serum-free media. We conclude that although the proteomic profiles of osteoblasts and MSCs show many similarities, we identified several osteoblast-specific extracellular matrix proteins and an osteoblast-specific intracellular signaling network. Therapeutic targeting of these proteins will possibly have minor effects on MSCs. Furthermore, the use of ex vivo cultured osteoblasts/MSCs in clinical medicine will require careful standardization of the ex vivo handling of the cells. Full article

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

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21 pages, 7422 KiB

Open AccessArticle

CD34+ Stromal Cells/Telocytes as a Source of Cancer-Associated Fibroblasts (CAFs) in Invasive Lobular Carcinoma of the Breast

by Lucio Díaz-Flores, Ricardo Gutiérrez, Miriam González-Gómez, Maria Pino García, Lucio Díaz-Flores, Jr., José Luís Carrasco and Pablo Martín-Vasallo

Int. J. Mol. Sci. 2021, 22(7), 3686; https://doi.org/10.3390/ijms22073686 - 1 Apr 2021

Cited by 21 | Viewed by 2741

Abstract

Several origins have been proposed for cancer-associated fibroblasts (CAFs), including resident CD34+ stromal cells/telocytes (CD34+SCs/TCs). The characteristics and arrangement of mammary CD34+SCs/TCs are well known and invasive lobular carcinoma of the breast (ILC) is one of the few malignant epithelial tumours with stromal cells that can express CD34 or αSMA, which could facilitate tracking these cells. Our objective is to assess whether tissue-resident CD34+SCs/TCs participate in the origin of CAFs in ILCs. For this purpose, using conventional and immunohistochemical procedures, we studied stromal cells in ILCs (n:42) and in normal breasts (n:6, also using electron microscopy). The results showed (a) the presence of anti-CD34+ or anti-αSMA+ stromal cells in varying proportion (from very rare in one of the markers to balanced) around nests/strands of neoplastic cells, (b) a similar arrangement and location of stromal cells in ILC to CD34+SCs/TCs in the normal breast, (c) both types of stromal cells coinciding around the same nest of neoplastic cells and (d) the coexpression of CD34 and αSMA in stromal cells in ILC. In conclusion, our findings support the hypothesis that resident CD34+SCs/TCs participate as an important source of CAFs in ILC. Further studies are required in this regard in other tumours. Full article

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

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17 pages, 3305 KiB

Open AccessArticle

Bone Marrow-Mesenchymal Stromal Cell Secretome as Conditioned Medium Relieves Experimental Skeletal Muscle Damage Induced by Ex Vivo Eccentric Contraction

by Roberta Squecco, Alessia Tani, Flaminia Chellini, Rachele Garella, Eglantina Idrizaj, Irene Rosa, Sandra Zecchi-Orlandini, Mirko Manetti and Chiara Sassoli

Int. J. Mol. Sci. 2021, 22(7), 3645; https://doi.org/10.3390/ijms22073645 - 31 Mar 2021

Cited by 11 | Viewed by 2806

Abstract

Bone marrow-mesenchymal stem/stromal cells (MSCs) may offer promise for skeletal muscle repair/regeneration. Growing evidence suggests that the mechanisms underpinning the beneficial effects of such cells in muscle tissue reside in their ability to secrete bioactive molecules (secretome) with multiple actions. Hence, we examined the effects of MSC secretome as conditioned medium (MSC-CM) on ex vivo murine extensor digitorum longus muscle injured by forced eccentric contraction (EC). By combining morphological (light and confocal laser scanning microscopies) and electrophysiological analyses we demonstrated the capability of MSC-CM to attenuate EC-induced tissue structural damages and sarcolemnic functional properties’ modifications. MSC-CM was effective in protecting myofibers from apoptosis, as suggested by a reduced expression of pro-apoptotic markers, cytochrome c and activated caspase-3, along with an increase in the expression of pro-survival AKT factor. Notably, MSC-CM also reduced the EC-induced tissue redistribution and extension of telocytes/CD34⁺ stromal cells, distinctive cells proposed to play a “nursing” role for the muscle resident myogenic satellite cells (SCs), regarded as the main players of regeneration. Moreover, it affected SC functionality likely contributing to replenishment of the SC reservoir. This study provides the necessary groundwork for further investigation of the effects of MSC secretome in the setting of skeletal muscle injury and regenerative medicine. Full article

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

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20 pages, 3716 KiB

Open AccessArticle

Why Do Muse Stem Cells Present an Enduring Stress Capacity? Hints from a Comparative Proteome Analysis

by Mustafa B. Acar, Domenico Aprile, Serife Ayaz-Guner, Huseyin Guner, Coskun Tez, Giovanni Di Bernardo, Gianfranco Peluso, Servet Ozcan and Umberto Galderisi

Int. J. Mol. Sci. 2021, 22(4), 2064; https://doi.org/10.3390/ijms22042064 - 19 Feb 2021

Cited by 11 | Viewed by 3867

Abstract

Muse cells are adult stem cells that are present in the stroma of several organs and possess an enduring capacity to cope with endogenous and exogenous genotoxic stress. In cell therapy, the peculiar biological properties of Muse cells render them a possible natural alternative to mesenchymal stromal cells (MSCs) or to in vitro-generated pluripotent stem cells (iPSCs). Indeed, some studies have proved that Muse cells can survive in adverse microenvironments, such as those present in damaged/injured tissues. We performed an evaluation of Muse cells’ proteome under basic conditions and followed oxidative stress treatment in order to identify ontologies, pathways, and networks that can be related to their enduring stress capacity. We executed the same analysis on iPSCs and MSCs, as a comparison. The Muse cells are enriched in several ontologies and pathways, such as endosomal vacuolar trafficking related to stress response, ubiquitin and proteasome degradation, and reactive oxygen scavenging. In Muse cells, the protein–protein interacting network has two key nodes with a high connectivity degree and betweenness: NFKB and CRKL. The protein NFKB is an almost-ubiquitous transcription factor related to many biological processes and can also have a role in protecting cells from apoptosis during exposure to a variety of stressors. CRKL is an adaptor protein and constitutes an integral part of the stress-activated protein kinase (SAPK) pathway. The identified pathways and networks are all involved in the quality control of cell components and may explain the stress resistance of Muse cells. Full article

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

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25 pages, 4461 KiB

Open AccessArticle

The Role of the FOXO1/β₂-AR/p-NF-κB p65 Pathway in the Development of Endometrial Stromal Cells in Pregnant Mice under Restraint Stress

by Jiayin Lu, Yaoxing Chen, Zixu Wang, Jing Cao and Yulan Dong

Int. J. Mol. Sci. 2021, 22(3), 1478; https://doi.org/10.3390/ijms22031478 - 2 Feb 2021

Cited by 6 | Viewed by 3464

Abstract

Restraint stress causes various maternal diseases during pregnancy. β₂-Adrenergic receptor (β₂-AR) and Forkhead transcription factor class O 1 (FOXO1) are critical factors not only in stress, but also in reproduction. However, the role of FOXO1 in restraint stress, causing changes in the β₂-AR pathway in pregnant mice, has been unclear. The aim of this research was to investigate the β₂-AR pathway of restraint stress and its impact on the oxidative stress of the maternal uterus. In the study, maternal mice were treated with restraint stress by being restrained in a transparent and ventilated device before sacrifice on Pregnancy Day 5 (P5), Pregnancy Day 10 (P10), Pregnancy Day 15 (P15), and Pregnancy Day 20 (P20) as well as on Non-Pregnancy Day 5 (NP5). Restraint stress augmented blood corticosterone (CORT), norepinephrine (NE), and blood glucose levels, while oestradiol (E2) levels decreased. Moreover, restraint stress increased the mRNA levels of the FOXO family, β₂-AR, and even the protein levels of FOXO1 and β₂-AR in the uterus and ovaries. Furthermore, restraint stress increased uterine oxidative stress level. In vitro, the protein levels of FOXO1 were also obviously increased when β₂-AR was activated in endometrial stromal cells (ESCs). In addition, phosphorylated-nuclear factor kappa-B p65 (p-NF-κB p65) and its target genes decreased significantly when FOXO1 was inhibited. Overall, it can be said that the β₂-AR/FOXO1/p-NF-κB p65 pathway was activated when pregnant mice were under restraint stress. This study provides a scientific basis for the origin of psychological stress in pregnant women. Full article

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

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Review

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33 pages, 1466 KiB

Open AccessReview

Angiogenic Effects and Crosstalk of Adipose-Derived Mesenchymal Stem/Stromal Cells and Their Extracellular Vesicles with Endothelial Cells

by Swarna Rautiainen, Timo Laaksonen and Raili Koivuniemi

Int. J. Mol. Sci. 2021, 22(19), 10890; https://doi.org/10.3390/ijms221910890 - 8 Oct 2021

Cited by 48 | Viewed by 5360

Abstract

Adipose-derived mesenchymal stem/stromal cells (ASCs) are an adult stem cell population able to self-renew and differentiate into numerous cell lineages. ASCs provide a promising future for therapeutic angiogenesis due to their ability to promote blood vessel formation. Specifically, their ability to differentiate into endothelial cells (ECs) and pericyte-like cells and to secrete angiogenesis-promoting growth factors and extracellular vesicles (EVs) makes them an ideal option in cell therapy and in regenerative medicine in conditions including tissue ischemia. In recent angiogenesis research, ASCs have often been co-cultured with an endothelial cell (EC) type in order to form mature vessel-like networks in specific culture conditions. In this review, we introduce co-culture systems and co-transplantation studies between ASCs and ECs. In co-cultures, the cells communicate via direct cell–cell contact or via paracrine signaling. Most often, ASCs are found in the perivascular niche lining the vessels, where they stabilize the vascular structures and express common pericyte surface proteins. In co-cultures, ASCs modulate endothelial cells and induce angiogenesis by promoting tube formation, partly via secretion of EVs. In vivo co-transplantation of ASCs and ECs showed improved formation of functional vessels over a single cell type transplantation. Adipose tissue as a cell source for both mesenchymal stem cells and ECs for co-transplantation serves as a prominent option for therapeutic angiogenesis and blood perfusion in vivo. Full article

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

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28 pages, 9748 KiB

Open AccessReview

Cd34+ Stromal Cells/Telocytes in Normal and Pathological Skin

by Lucio Díaz-Flores, Ricardo Gutiérrez, Maria Pino García, Miriam González-Gómez, Rosa Rodríguez-Rodriguez, Nieves Hernández-León, Lucio Díaz-Flores, Jr. and José Luís Carrasco

Int. J. Mol. Sci. 2021, 22(14), 7342; https://doi.org/10.3390/ijms22147342 - 8 Jul 2021

Cited by 31 | Viewed by 4014

Abstract

We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other authors in the normal dermis regarding CD34+SC/TC characteristics and distribution around vessels, nerves and cutaneous annexes, highlighting their practical absence in the papillary dermis and presence in the bulge region of perifollicular groups of very small CD34+ stromal cells. In non-tumoral skin pathology, we studied examples of the principal histologic patterns in which CD34+SCs/TCs have (1) a fundamental pathophysiological role, including (a) fibrosing/sclerosing diseases, such as systemic sclerosis, with loss of CD34+SCs/TCs and presence of stromal cells co-expressing CD34 and αSMA, and (b) metabolic degenerative processes, including basophilic degeneration of collagen, with stromal cells/telocytes in close association with degenerative fibrils, and cutaneous myxoid cysts with spindle-shaped, stellate and bulky vacuolated CD34+ stromal cells, and (2) a secondary reactive role, encompassing dermatitis—e.g., interface (erythema multiforme), acantholytic (pemphigus, Hailey–Hailey disease), lichenoid (lichen planus), subepidermal vesicular (bullous pemphigoid), psoriasiform (psoriasis), granulomatous (granuloma annulare)—vasculitis (leukocytoclastic and lymphocytic vasculitis), folliculitis, perifolliculitis and inflammation of the sweat and sebaceous glands (perifolliculitis and rosacea) and infectious dermatitis (verruca vulgaris). In skin tumor and tumor-like conditions, we studied examples of those in which CD34+ stromal cells are (1) the neoplastic component (dermatofibrosarcoma protuberans, sclerotic fibroma and solitary fibrous tumor), (2) a neoplastic component with varying presentation (fibroepithelial polyp and superficial myxofibrosarcoma) and (3) a reactive component in other tumor/tumor-like cell lines, such as those deriving from vessel periendothelial cells (myopericytoma), epithelial cells (trichoepithelioma, nevus sebaceous of Jadassohn and seborrheic keratosis), Merkel cells (Merkel cell carcinoma), melanocytes (dermal melanocytic nevi) and Schwann cells (neurofibroma and granular cell tumor). Full article

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

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18 pages, 780 KiB

Open AccessReview

Migration and Adhesion of B-Lymphocytes to Specific Microenvironments in Mantle Cell Lymphoma: Interplay between Signaling Pathways and the Epigenetic Landscape

by Laia Sadeghi and Anthony P. Wright

Int. J. Mol. Sci. 2021, 22(12), 6247; https://doi.org/10.3390/ijms22126247 - 10 Jun 2021

Cited by 6 | Viewed by 3277

Abstract

Lymphocyte migration to and sequestration in specific microenvironments plays a crucial role in their differentiation and survival. Lymphocyte trafficking and homing are tightly regulated by signaling pathways and is mediated by cytokines, chemokines, cytokine/chemokine receptors and adhesion molecules. The production of cytokines and chemokines is largely controlled by transcription factors in the context of a specific epigenetic landscape. These regulatory factors are strongly interconnected, and they influence the gene expression pattern in lymphocytes, promoting processes such as cell survival. The epigenetic status of the genome plays a key role in regulating gene expression during many key biological processes, and it is becoming more evident that dysregulation of epigenetic mechanisms contributes to cancer initiation, progression and drug resistance. Here, we review the signaling pathways that regulate lymphoma cell migration and adhesion with a focus on Mantle cell lymphoma and highlight the fundamental role of epigenetic mechanisms in integrating signals at the level of gene expression throughout the genome. Full article

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

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