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Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 32974

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Special Issue Editors

Dr. Alessandra Colombini

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Orthopaedic Biotechnology Lab, IRCCS Ospedale Galeazzi-Sant'Ambrogio, Via Cristina Belgioioso 173, 20157 Milan, MI, Italy
Interests: orthopedics; musculoskeletal field; mesenchymal stem/stromal cells; regenerative medicine; clinical biochemistry
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Dr. Enrico Ragni

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Laboratorio di Biotecnologie Applicate All'Ortopedia, IRCCS Ospedale Galeazzi–Sant’Ambrogio, Via Cristina Belgioioso 173, 20157 Milan, Italy
Interests: regenerative medicine; mesenchymal stromal cells; osteoarthritis; extracellular vesicles; miRNA
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Dr. Silvia Lopa

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Cell and Tissue Engineering Laboratory, IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy
Interests: advanced in vitro models; inflammation; arthritis; mesenchymal stem cells

Special Issue Information

Dear Colleagues,

The unstoppable progression of knowledge of the pathophysiological processes affecting bony, articular, and muscular structures allows for the continuous identification of new therapeutic targets and agents to be exploited in addressing the degenerative mechanisms affecting the musculoskeletal system.

The ultimate goal is to validate the results of in vitro studies in preclinical in vivo models, and subsequently translate the most promising therapies to clinical practice. The cutting-edge approaches are multiple, from the development of advanced in vitro models for the study of pathophysiological process to the implementation of cell-based therapies, including those that only involve cell paracrine activity or the combination of cells and scaffolds in tissue engineering approaches. In this context, progenitor cells, either stem or tissue specific, are fundamental as both actors and as in situ targets, due to their ability to promote a trophic and anti-inflammatory microenvironment.

The purpose of this Special Issue is to collect reports concerning advances in musculoskeletal cell therapy to drive researchers and clinicians towards innovative perspectives for the treatment of degenerative orthopaedic diseases.

Dr. Alessandra Colombini
Dr. Enrico Ragni
Dr. Silvia Lopa
Guest Editors

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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

orthopaedics
stem cells
progenitors
regenerative medicine
clinical translation
bioengineering
in vitro models
cell-free approaches

Published Papers (10 papers)

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Editorial

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3 pages, 196 KiB

Open AccessEditorial

Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches

by Enrico Ragni, Alessandra Colombini and Silvia Lopa

Cells 2022, 11(23), 3858; https://doi.org/10.3390/cells11233858 - 30 Nov 2022

Cited by 1 | Viewed by 897

Abstract

Nowadays, the real need in orthopedic research is to strictly validate advanced regenerative medicine approaches in preclinical models, with the hope that this unique and straightforward approach can facilitate a safe and effective translation into everyday clinical practice [...] Full article

(This article belongs to the Special Issue Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches)

Research

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14 pages, 5834 KiB

Open AccessArticle

Association between Oncostatin M Expression and Inflammatory Phenotype in Experimental Arthritis Models and Osteoarthritis Patients

by Joao Pedro Garcia, Lizette Utomo, Imke Rudnik-Jansen, Jie Du, Nicolaas P.A. Zuithoff, Anita Krouwels, Gerjo J.V.M. van Osch and Laura B. Creemers

Cells 2021, 10(3), 508; https://doi.org/10.3390/cells10030508 - 27 Feb 2021

Cited by 13 | Viewed by 2720

Abstract

Pro-inflammatory cytokines are considered to play a major role in osteoarthritis (OA), yet so far, the specific cytokines involved in the pathology of OA have not been identified. Oncostatin M (OSM) is a cytokine from the interleukin 6 (IL-6) family that has been shown to be elevated in synovial fluid of most rheumatoid arthritis (RA) patients, but only in a limited subset of OA patients. Little is known about OSM in the different joint tissues during OA and how its expression correlates with hallmarks of disease. Here, we mapped OSM expression in the joint tissues of two rat models of arthritis: an acute inflammatory model and an instability-induced osteoarthritic model. OSM expression was correlated with hallmarks of OA, namely cartilage damage, synovitis, and osteophyte formation. Reanalysis of an existing dataset on cytokine profiling of OA synovial fluid was performed to assess pattern differences between patients positive and negative for OSM. In the inflammatory model, OSM expression correlated with synovitis and osteophyte formation but not with cartilage damage. On the contrary, in the instability model of OA, an increase in synovitis, cartilage damage, and osteophyte formation was observed without changes in OSM expression. In line with these findings, synovial fluid of OA patients with detectable OSM contained higher levels of other inflammatory cytokines, namely interferon gamma (IFN-γ), IL-1α and tumor necrosis factor alpha (TNF-α), likely indicating a more inflammatory state. Taken together these data indicate OSM might play a prominent role in inflammatory phenotypes of OA. Full article

(This article belongs to the Special Issue Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches)

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20 pages, 2451 KiB

Open AccessArticle

Administration of Human Non-Diabetic Mesenchymal Stromal Cells to a Murine Model of Diabetic Fracture Repair: A Pilot Study

by Luke Watson, Xi Zhe Chen, Aideen E. Ryan, Áine Fleming, Aoife Carbin, Lisa O’Flynn, Paul G. Loftus, Emma Horan, David Connolly, Patrick McDonnell, Laoise M. McNamara, Timothy O’Brien and Cynthia M. Coleman

Cells 2020, 9(6), 1394; https://doi.org/10.3390/cells9061394 - 3 Jun 2020

Cited by 4 | Viewed by 2424

Abstract

Individuals living with type 1 diabetes mellitus may experience an increased risk of long bone fracture. These fractures are often slow to heal, resulting in delayed reunion or non-union. It is reasonable to theorize that the underlying cause of these diabetes-associated osteopathies is faulty repair dynamics as a result of compromised bone marrow progenitor cell function. Here it was hypothesized that the administration of non-diabetic, human adult bone marrow-derived mesenchymal stromal cells (MSCs) would enhance diabetic fracture healing. Human MSCs were locally introduced to femur fractures in streptozotocin-induced diabetic mice, and the quality of de novo bone was assessed eight weeks later. Biodistribution analysis demonstrated that the cells remained in situ for three days following administration. Bone bridging was evident in all animals. However, a large reparative callus was retained, indicating non-union. µCT analysis elucidated comparable callus dimensions, bone mineral density, bone volume/total volume, and volume of mature bone in all groups that received cells as compared to the saline-treated controls. Four-point bending evaluation of flexural strength, flexural modulus, and total energy to re-fracture did not indicate a statistically significant change as a result of cellular administration. An ex vivo lymphocytic proliferation recall assay indicated that the xenogeneic administration of human cells did not result in an immune response by the murine recipient. Due to this dataset, the administration of non-diabetic bone marrow-derived MSCs did not support fracture healing in this pilot study. Full article

(This article belongs to the Special Issue Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches)

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17 pages, 3411 KiB

Open AccessArticle

Innovative Visualization and Quantification of Extracellular Vesicles Interaction with and Incorporation in Target Cells in 3D Microenvironments

by Enrico Ragni, Silvia Palombella, Silvia Lopa, Giuseppe Talò, Carlotta Perucca Orfei, Paola De Luca, Matteo Moretti and Laura de Girolamo

Cells 2020, 9(5), 1180; https://doi.org/10.3390/cells9051180 - 9 May 2020

Cited by 17 | Viewed by 3459

Abstract

Extracellular vesicles (EVs) showed therapeutic properties in several applications, many in regenerative medicine. A clear example is in the treatment of osteoarthritis (OA), where adipose-derived mesenchymal stem cells (ASCs)-EVs were able to promote regeneration and reduce inflammation in both synovia and cartilage. A still obscure issue is the effective ability of EVs to be internalized by target cells, rather than simply bound to the extracellular matrix (ECM) or plasma membrane, since the current detection or imaging technologies cannot fully decipher it due to technical limitations. In the present study, human articular chondrocytes (ACHs) and fibroblast-like synoviocytes (FLSs) isolated from the same OA patients were cocultured in 2D as well as in 3D conditions with fluorescently labeled ASC-EVs, and analyzed by flow cytometry or confocal microscopy, respectively. In contrast with conventional 2D, in 3D cultures, confocal microscopy allowed a clear detection of the tridimensional morphology of the cells and thus an accurate discrimination of EV interaction with the external and/or internal cell environment. In both 2D and 3D conditions, FLSs were more efficient in interacting with ASC-EVs and 3D imaging demonstrated a faster uptake process. The removal of the hyaluronic acid component from the ECM of both cell types reduced their interaction with ASC-EVs only in the 2D system, showing that 2D and 3D conditions can yield different outcomes when investigating events where ECM plays a key role. These results indicate that studying EVs binding and uptake both in 2D and 3D guarantees a more precise and complementary characterization of the molecular mechanisms involved in the process. The implementation of this strategy can become a valuable tool not only for basic research, but also for release assays and potency prediction for clinical EV batches. Full article

(This article belongs to the Special Issue Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches)

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25 pages, 4496 KiB

Open AccessArticle

Progenitor Cells Activated by Platelet Lysate in Human Articular Cartilage as a Tool for Future Cartilage Engineering and Reparative Strategies

by Simonetta Carluccio, Daniela Martinelli, Maria Elisabetta Federica Palamà, Rui Cruz Pereira, Roberto Benelli, Ana Guijarro, Ranieri Cancedda and Chiara Gentili

Cells 2020, 9(4), 1052; https://doi.org/10.3390/cells9041052 - 23 Apr 2020

Cited by 25 | Viewed by 4147

Abstract

Regenerative strategies for human articular cartilage are still challenging despite the presence of resident progenitor cell population. Today, many efforts in the field of regenerative medicine focus on the use of platelet derivatives due to their ability to reactivate endogenous mechanisms supporting tissue repair. While their use in orthopedics continues, mechanisms of action and efficacy need further characterization. We describe that the platelet lysate (PL) is able to activate chondro-progenitor cells in a terminally differentiated cartilage tissue. Primary cultures of human articular chondrocytes (ACs) and cartilage explants were set up from donor hip joint biopsies and were treated in vitro with PL. PL recruited a chondro-progenitors (CPCs)-enriched population from ex vivo cartilage culture, that showed high proliferation rate, clonogenicity and nestin expression. CPCs were positive for in vitro tri-lineage differentiation and formed hyaline cartilage-like tissue in vivo without hypertrophic fate. Moreover, the secretory profile of CPCs was analyzed, together with their migratory capabilities. Some CPC-features were also induced in PL-treated ACs compared to fetal bovine serum (FBS)-control ACs. PL treatment of human articular cartilage activates a stem cell niche responsive to injury. These facts can improve the PL therapeutic efficacy in cartilage applications. Full article

(This article belongs to the Special Issue Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches)

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15 pages, 4213 KiB

Open AccessArticle

Effect of Chemically Induced Hypoxia on Osteogenic and Angiogenic Differentiation of Bone Marrow Mesenchymal Stem Cells and Human Umbilical Vein Endothelial Cells in Direct Coculture

by Van Thi Nguyen, Barbara Canciani, Federica Cirillo, Luigi Anastasia, Giuseppe M. Peretti and Laura Mangiavini

Cells 2020, 9(3), 757; https://doi.org/10.3390/cells9030757 - 19 Mar 2020

Cited by 22 | Viewed by 4378

Abstract

Bone is an active tissue where bone mineralization and resorption occur simultaneously. In the case of fracture, there are numerous factors required to facilitate bone healing including precursor cells and blood vessels. To evaluate the interaction between bone marrow-derived mesenchymal stem cells (BMSC)—the precursor cells able to differentiate into bone-forming cells and human umbilical vein endothelial cells (HUVEC)—a cell source widely used for the study of blood vessels. We performed direct coculture of BMSC and HUVEC in normoxia and chemically induced hypoxia using Cobalt(II) chloride and Dimethyloxaloylglycine and in the condition where oxygen level was maintained at 1% as well. Cell proliferation was analyzed by crystal violet staining. Osteogenesis was examined by Alizarin Red and Collagen type I staining. Expression of angiogenic factor-vascular endothelial growth factor (VEGF) and endothelial marker-von Willebrand factor (VWF) were demonstrated by immunohistochemistry and enzyme-linked immunosorbent assay. The quantitative polymerase chain reaction was also used to evaluate gene expression. The results showed that coculture in normoxia could retain both osteogenic differentiation and endothelial markers while hypoxic condition limits cell proliferation and osteogenesis but favors the angiogenic function even after 1 of day treatment. Full article

(This article belongs to the Special Issue Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches)

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12 pages, 2932 KiB

Open AccessArticle

Treatment with Human Amniotic Suspension Allograft Improves Tendon Healing in a Rat Model of Collagenase-Induced Tendinopathy

by Laura de Girolamo, Luiz Felipe Morlin Ambra, Carlotta Perucca Orfei, John P. McQuilling, Kelly A. Kimmerling, Katie C. Mowry, Kimberly A. Johnson, Amy T. Phan, Jessica L. Whited and Andreas H. Gomoll

Cells 2019, 8(11), 1411; https://doi.org/10.3390/cells8111411 - 8 Nov 2019

Cited by 18 | Viewed by 3291

Abstract

Treatment of tendon injuries is challenging, with neither conservative nor surgical approaches providing full recovery. Placental-derived tissues represent a promising tool for the treatment of tendon injuries. In this study, human amniotic suspension allograft (ASA) was investigated in a pre-clinical model of Achilles tendinopathy. Collagenase type I was injected in the right hind limb of Sprague Dawley rats to induce disease. Contralateral tendons were either left untreated or injected with saline as controls. Seven days following induction, tendons were injected with saline, ASA, or left untreated. Rats were sacrificed 14 and 28 days post-treatment. Histological and biomechanical analysis of tendons was completed. Fourteen days after ASA injection, improved fiber alignment and reduced cell density demonstrated improvement in degenerated tendons. Twenty-eight days post-treatment, tendons in all treatment groups showed fewer signs of degeneration, which is consistent with normal tendon healing. No statistically significant differences in histological or biomechanical analyses were observed between treatment groups at 28 days independent of the treatment they received. In this study, ASA treatment was safe, well-tolerated, and resulted in a widespread improvement of the tissue. The results of this study provide preliminary insights regarding the potential use of ASA for the treatment of Achilles tendinopathy. Full article

(This article belongs to the Special Issue Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches)

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12 pages, 1525 KiB

Open AccessArticle

Reliable Reference Genes for Gene Expression Assessment in Tendon-Derived Cells under Inflammatory and Pro-Fibrotic/Healing Stimuli

by Enrico Ragni, Carlotta Perucca Orfei, Annie C. Bowles, Laura de Girolamo and Diego Correa

Cells 2019, 8(10), 1188; https://doi.org/10.3390/cells8101188 - 1 Oct 2019

Cited by 9 | Viewed by 3356

Abstract

Tendon cells (TCs) are important for homeostatic maintenance in the healthy tendon and to promote tissue healing after injury. Further, resident and rare populations of tendon stem/progenitor cells, located at various sites within the tendon, contribute to tendon recovery by differentiating into repairing TCs. Gene expression analysis, through quantitative reverse-transcription polymerase chain reaction (qRT-PCR), constitutes a useful tool to study cellular responses, including the transition from initial inflammation to healing processes. A critical step required for data normalization is the choice of reliable reference genes (RGs), a process highly underestimated in tendon biology. In this study, the suitability of five commonly used RGs (ACTB, B2M, GAPDH, HPRT1, and RPLP0) was evaluated using TCs samples cultured in both standard and progenitor-enriching conditions, as well as under either inflammatory (IFNγ + TNFα) or pro-fibrotic/healing (CTGF) stimulation. The stability of the candidate RGs was computationally determined using NormFinder, geNorm, BestKeeper, and DeltaCt applets. Overall, ACTB resulted as the most stable RG on the basis of the integration of each gene weight, whereas B2M and RPLP0 performed poorly. To further validate ACTB’s optimal performance, we evaluated the expression of ICAM1, coding for an immune-related cell surface glycoprotein, and COL1A1, encoding collagen type I that is the main component of the tendon extracellular matrix (ECM), both known to be modulated by inflammation. The expression of both genes was heavily affected by the RGs used. Consequently, when analyzing gene expression in tendon-derived cells subjected to various stimulatory protocols, the use of a suitable RG should be considered carefully. On the basis of our results, ACTB can be reliably used when analyzing different TC types exposed to pathological conditions. Full article

(This article belongs to the Special Issue Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches)

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Review

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20 pages, 1093 KiB

Open AccessReview

Umbilical Cord MSCs and Their Secretome in the Therapy of Arthritic Diseases: A Research and Industrial Perspective

by Chiara Arrigoni, Daniele D’Arrigo, Valeria Rossella, Christian Candrian, Veronica Albertini and Matteo Moretti

Cells 2020, 9(6), 1343; https://doi.org/10.3390/cells9061343 - 28 May 2020

Cited by 19 | Viewed by 4074

Abstract

The prevalence of arthritic diseases is increasing in developed countries, but effective treatments are currently lacking. The injection of mesenchymal stem cells (MSCs) represents a promising approach to counteract the degenerative and inflammatory environment characterizing those pathologies, such as osteoarthritis (OA). However, the majority of clinical approaches based on MSCs are used within an autologous paradigm, with important limitations. For this reason, allogeneic MSCs isolated from cord blood (cbMSCs) and Wharton’s jelly (wjMSCs) gained increasing interest, demonstrating promising results in this field. Moreover, recent evidences shows that MSCs beneficial effects can be related to their secretome rather than to the presence of cells themselves. Among the trophic factors secreted by MSCs, extracellular vesicles (EVs) are emerging as a promising candidate for the treatment of arthritic joints. In the present review, the application of umbilical cord MSCs and their secretome as innovative therapeutic approaches in the treatment of arthritic joints will be examined. With the prospective of routine clinical applications, umbilical cord MSCs and EVs will be discussed also within an industrial and regulatory perspective. Full article

(This article belongs to the Special Issue Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches)

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Other

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27 pages, 8719 KiB

Open AccessCase Report

Co-Transplantation of Bone Marrow-MSCs and Myogenic Stem/Progenitor Cells from Adult Donors Improves Muscle Function of Patients with Duchenne Muscular Dystrophy

by Aleksandra Klimczak, Agnieszka Zimna, Agnieszka Malcher, Urszula Kozlowska, Katarzyna Futoma, Jaroslaw Czarnota, Pawel Kemnitz, Anna Bryl and Maciej Kurpisz

Cells 2020, 9(5), 1119; https://doi.org/10.3390/cells9051119 - 30 Apr 2020

Cited by 14 | Viewed by 3349

Abstract

Duchenne muscular dystrophy (DMD) is a genetic disorder associated with a progressive deficiency of dystrophin that leads to skeletal muscle degeneration. In this study, we tested the hypothesis that a co-transplantation of two stem/progenitor cell populations, namely bone marrow-derived mesenchymal stem cells (BM-MSCs) and skeletal muscle-derived stem/progenitor cells (SM-SPCs), directly into the dystrophic muscle can improve the skeletal muscle function of DMD patients. Three patients diagnosed with DMD, confirmed by the dystrophin gene mutation, were enrolled into a study approved by the local Bioethics Committee (no. 79/2015). Stem/progenitor cells collected from bone marrow and skeletal muscles of related healthy donors, based on HLA matched antigens, were expanded in a closed MC3 cell culture system. A simultaneous co-transplantation of BM-MSCs and SM-SPCs was performed directly into the biceps brachii (two patients) and gastrocnemius (one patient). During a six-month follow-up, the patients were examined with electromyography (EMG) and monitored for blood kinase creatine level. Muscle biopsies were examined with histology and assessed for dystrophin at the mRNA and protein level. A panel of 27 cytokines was analysed with multiplex ELISA. We did not observe any adverse effects after the intramuscular administration of cells. The efficacy of BM-MSC and SM-SPC application was confirmed through an EMG assessment by an increase in motor unit parameters, especially in terms of duration, amplitude range, area, and size index. The beneficial effect of cellular therapy was confirmed by a decrease in creatine kinase levels and a normalised profile of pro-inflammatory cytokines. BM-MSCs may support the pro-regenerative potential of SM-SPCs thanks to their trophic, paracrine, and immunomodulatory activity. Both applied cell populations may fuse with degenerating skeletal muscle fibres in situ, facilitating skeletal muscle recovery. However, further studies are required to optimise the dose and timing of stem/progenitor cell delivery. Full article

(This article belongs to the Special Issue Advances in Musculoskeletal Cell Therapy: Basic Science and Translational Approaches)

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