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Stem/Progenitor Cells for Musculoskeletal Disease Modeling and Tissue Repair

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A special issue of Bioengineering (ISSN 2306-5354). This special issue belongs to the section "Regenerative Engineering".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 18485

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Special Issue Editors

Dr. Zhong Li

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Guest Editor

Department of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong, China
Interests: tissue chips; biomaterials; stem cell; tissue engineering; regenerative medicine

Dr. Wanting Niu

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Guest Editor

Tissue Engineering Labs, VA Boston Healthcare System & Department of Orthopedics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Interests: biomaterials; stem cells; tissue engineering and regerenative medicine; cartilage and bone repair; central neural system repair

Special Issue Information

Dear Colleagues,

Progenitor/stem cells have promising applications in the repair and regeneration of bone, cartilage, skeletal muscle, tendon, and ligament. To fully unleash their clinical potential, mechanistic studies on their differentiation and regeneration capabilities are warranted. In addition, investigations of musculoskeletal pathophysiology require physiologically relevant models which are expected to overcome the limitations of conventional 2D and 3D cell cultures and animal models. In this regard, organoids and tissue chips engineered from stem cells promise to offer effective preclinical models for simulating the in vivo physiology of healthy or diseased tissues and predicting native tissues’ responses to various drugs and other treatments.

The Special Issue on “Stem/Progenitor Cells for Musculoskeletal Disease Modeling and Tissue Repair” welcomes both original research papers and comprehensive reviews covering orthopedic applications of stem/progenitor cells, emphasizing an enhanced understanding of the mechanisms responsible for disease development and tissue regeneration. Topics of interest in this Special Issue include but are not limited to the following，

Stem cell-derived organoids and tissue chips (microphysiological systems) for modeling musculoskeletal disorders and evaluating drug efficacy;
Molecular mechanisms underlying musculoskeletal tissue repair by mesenchymal stem cells, skeletal stem cells, and induced pluripotent stem cells;
Biomaterials, scaffolds, and advanced fabrication techniques that enhance the differentiation and regenerative capabilities of stem cells in musculoskeletal applications;
Optimization of induced pluripotent stem cell differentiation into musculoskeletal lineages;
Progenitor/stem cell-derived exosomes and extracellular vesicles in promoting musculoskeletal tissue repair;
Role of mechanical stimulation and other biophysical cues in stem cell lineage specification and musculoskeletal tissue regeneration.

Dr. Zhong Li
Dr. Wanting Niu
Guest Editors

Manuscript Submission Information

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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

mesenchymal stem cells/stromal cells
induced pluripotent stem cells
orthopedics
tissue engineering
organoid
bioreactor
microphysiological system
organ-on-a-chip
extracellular vesicles
biofabrication

Published Papers (6 papers)

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Research

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21 pages, 5251 KiB

Open AccessArticle

Anti-Apoptosis Therapy for Meniscal Avascular Zone Repair: A Proof-of-Concept Study in a Lapine Model

by Wenqiang Yan, Yue Wu, Fengyuan Zhao, Ruilan Dai, Yunan Zhou, Dingge Liu, Jin Cheng, Xiaoqing Hu and Yingfang Ao

Bioengineering 2023, 10(12), 1422; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering10121422 - 14 Dec 2023

Viewed by 823

Abstract

In the present study, 24 rabbits were firstly used to evaluate the apoptosis index and matrix degeneration after untreated adult meniscal tears. Vertical tears (0.25 cm in length) were prepared in the avascular zone of the anterior horn. Specimens were harvested at 1, 3, 6, 12 weeks postoperatively. The apoptosis index around tear sites stayed at a high level throughout the whole follow-up period. The depletion of glycosaminoglycans (GAG) and aggrecan at the tear site was observed, while the deposition of COL I and COL II was not affected, even at the last follow-up of 12 weeks after operation. The expression of SOX9 decreased significantly; no cellularity was observed at the wound interface at all timepoints. Secondly, another 20 rabbits were included to evaluate the effects of anti-apoptosis therapy on rescuing meniscal cells and enhancing meniscus repair. Longitudinal vertical tears (0.5 cm in length) were made in the meniscal avascular body. Tears were repaired by the inside-out suture technique, or repaired with sutures in addition to fibrin gel and blank silica nanoparticles, or silica nanoparticles encapsulating apoptosis inhibitors (z-vad-fmk). Samples were harvested at 12 months postoperatively. We found the locally administered z-vad-fmk agent at the wound interface significantly alleviated meniscal cell apoptosis and matrix degradation, and enhanced meniscal repair in the avascular zone at 12 months after operation. Thus, local administration of caspase inhibitors (z-vad-fmk) is a promising therapeutic strategy for alleviating meniscal cell loss and enhancing meniscal repair after adult meniscal tears in the avascular zone. Full article

(This article belongs to the Special Issue Stem/Progenitor Cells for Musculoskeletal Disease Modeling and Tissue Repair)

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17 pages, 6269 KiB

Open AccessArticle

Chondroprotective Effects of Chondrogenic Differentiated Adipose-Derived Mesenchymal Stem Cells Sheet on Degenerated Articular Cartilage in an Experimental Rabbit Model

by Atsushi Taninaka, Tamon Kabata, Katsuhiro Hayashi, Yoshitomo Kajino, Daisuke Inoue, Takaaki Ohmori, Ken Ueoka, Yuki Yamamuro, Tomoyuki Kataoka, Yoshitomo Saiki, Yu Yanagi, Musashi Ima, Takahiro Iyobe and Hiroyuki Tsuchiya

Bioengineering 2023, 10(5), 574; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering10050574 - 10 May 2023

Cited by 1 | Viewed by 1525

Abstract

Adipose-derived stem cells (ADSCs) have been studied for many years as a therapeutic option for osteoarthritis (OA); however, their efficacy remains insufficient. Since platelet-rich plasma (PRP) induces chondrogenic differentiation in ADSCs and the formation of a sheet structure by ascorbic acid can increase the number of viable cells, we hypothesized that the injection of chondrogenic cell sheets combined with the effects of PRP and ascorbic acid may hinder the progression of OA. The effects of induction of differentiation by PRP and formation of sheet structure by ascorbic acid on changes in chondrocyte markers (collagen II, aggrecan, Sox9) in ADSCs were evaluated. Changes in mucopolysaccharide and VEGF-A secretion from cells injected intra-articularly in a rabbit OA model were also evaluated. ADSCs treated by PRP strongly chondrocyte markers, including type II collagen, Sox9, and aggrecan, and their gene expression was maintained even after sheet-like structure formation induced by ascorbic acid. In this rabbit OA model study, the inhibition of OA progression by intra-articular injection was improved by inducing chondrocyte differentiation with PRP and sheet structure formation with ascorbic acid in ADSCs. Full article

(This article belongs to the Special Issue Stem/Progenitor Cells for Musculoskeletal Disease Modeling and Tissue Repair)

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15 pages, 3304 KiB

Open AccessArticle

Platelet-Rich Plasma Lysate-Incorporating Gelatin Hydrogel as a Scaffold for Bone Reconstruction

by Meral Nadra, Wanting Niu, Motoichi Kurisawa, Dominique Rousson and Myron Spector

Bioengineering 2022, 9(10), 513; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering9100513 - 29 Sep 2022

Cited by 6 | Viewed by 1941

Abstract

In implant dentistry, large vertical and horizontal alveolar ridge deficiencies in mandibular and maxillary bone are challenges that clinicians continue to face. One of the limitations of porous blocks for reconstruction of bone in large defects in the oral cavity, and in the musculoskeletal system, is that fibrin clot does not adequately fill the interior pores and does not persist long enough to accommodate cell migration into the center of the block. The objective of our work was to develop a gelatin-based gel incorporating platelet-rich plasma (PRP) lysate, to mimic the role that a blood clot would normally play to attract and accommodate the migration of host osteoprogenitor and endothelial cells into the scaffold, thereby facilitating bone reconstruction. A conjugate of gelatin (Gtn) and hydroxyphenyl propionic acid (HPA), an amino-acid-like molecule, was commended for this application because of its ability to undergo enzyme-mediated covalent cross-linking to form a hydrogel in vivo, after being injected as a liquid. The initiation and propagation of cross-linking were under the control of horseradish peroxidase and hydrogen peroxide, respectively. The objectives of this in vitro study were directed toward evaluating: (1) the migration of rat mesenchymal stem cells (MSCs) into Gtn–HPA gel under the influence of rat PRP lysate or recombinant platelet-derived growth factor (PDGF)-BB incorporated into the gel; (2) the differentiation of MSCs, incorporated into the gel, into osteogenic cells under the influence of PRP lysate and PDGF-BB; and (3) the release kinetics of PDGF-BB from gels incorporating two formulations of PRP lysate and recombinant PDGF-BB. Results: The number of MSCs migrating into the hydrogel was significantly (3-fold) higher in the hydrogel group incorporating PRP lysate compared to the PDGF-BB and the blank gel control groups. For the differentiation/osteogenesis assay, the osteocalcin-positive cell area percentage was significantly higher in both the gel/PRP and gel/PDGF-BB groups, compared to the two control groups: cells in the blank gels grown in cell expansion medium and in osteogenic medium. Results of the ELISA release assay indicated that Gtn–HPA acted as an effective delivery vehicle for the sustained release of PDGF-BB from two different PRP lysate batches, with about 60% of the original PDGF-BB amount in the two groups remaining in the gel at 28 days. Conclusions: Gtn–HPA accommodates MSC migration. PRP-lysate-incorporating hydrogels chemoattract increased MSC migration into the Gtn–HPA compared to the blank gel. PRP-lysate- and the PDGF-BB-incorporating gels stimulate osteogenic differentiation of the MSCs. The release of the growth factors from Gtn–HPA containing PRP lysate can extend over the period of time (weeks) necessary for bone reconstruction. The findings demonstrate that Gtn–HPA can serve as both a scaffold for cell migration and a delivery vehicle that allows sustained and controlled release of the incorporated therapeutic agent over extended periods of time. These findings commend Gtn–HPA incorporating PRP lysate for infusion into porous calcium phosphate blocks for vertical and horizontal ridge reconstruction, and for other musculoskeletal applications. Full article

(This article belongs to the Special Issue Stem/Progenitor Cells for Musculoskeletal Disease Modeling and Tissue Repair)

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Review

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21 pages, 2348 KiB

Open AccessReview

The Developmental Implications of Muscle-Targeted Magnetic Mitohormesis: A Human Health and Longevity Perspective

by Alfredo Franco-Obregón, Yee Kit Tai, Kwan Yu Wu, Jan Nikolas Iversen and Craig Jun Kit Wong

Bioengineering 2023, 10(8), 956; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering10080956 - 12 Aug 2023

Cited by 2 | Viewed by 3264

Abstract

Muscle function reflects muscular mitochondrial status, which, in turn, is an adaptive response to physical activity, representing improvements in energy production for de novo biosynthesis or metabolic efficiency. Differences in muscle performance are manifestations of the expression of distinct contractile-protein isoforms and of mitochondrial-energy substrate utilization. Powerful contractures require immediate energy production from carbohydrates outside the mitochondria that exhaust rapidly. Sustained muscle contractions require aerobic energy production from fatty acids by the mitochondria that is slower and produces less force. These two patterns of muscle force generation are broadly classified as glycolytic or oxidative, respectively, and require disparate levels of increased contractile or mitochondrial protein production, respectively, to be effectively executed. Glycolytic muscle, hence, tends towards fibre hypertrophy, whereas oxidative fibres are more disposed towards increased mitochondrial content and efficiency, rather than hypertrophy. Although developmentally predetermined muscle classes exist, a degree of functional plasticity persists across all muscles post-birth that can be modulated by exercise and generally results in an increase in the oxidative character of muscle. Oxidative muscle is most strongly correlated with organismal metabolic balance and longevity because of the propensity of oxidative muscle for fatty-acid oxidation and associated anti-inflammatory ramifications which occur at the expense of glycolytic-muscle development and hypertrophy. This muscle-class size disparity is often at odds with common expectations that muscle mass should scale positively with improved health and longevity. Brief magnetic-field activation of the muscle mitochondrial pool has been shown to recapitulate key aspects of the oxidative-muscle phenotype with similar metabolic hallmarks. This review discusses the common genetic cascades invoked by endurance exercise and magnetic-field therapy and the potential physiological differences with regards to human health and longevity. Future human studies examining the physiological consequences of magnetic-field therapy are warranted. Full article

(This article belongs to the Special Issue Stem/Progenitor Cells for Musculoskeletal Disease Modeling and Tissue Repair)

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17 pages, 650 KiB

Open AccessReview

Applications of Ultrasound-Mediated Gene Delivery in Regenerative Medicine

by Zoe Krut, Dan Gazit, Zulma Gazit and Gadi Pelled

Bioengineering 2022, 9(5), 190; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering9050190 - 27 Apr 2022

Cited by 6 | Viewed by 3431

Abstract

Research on the capability of non-viral gene delivery systems to induce tissue regeneration is a continued effort as the current use of viral vectors can present with significant limitations. Despite initially showing lower gene transfection and gene expression efficiencies, non-viral delivery methods continue to be optimized to match that of their viral counterparts. Ultrasound-mediated gene transfer, referred to as sonoporation, occurs by the induction of transient membrane permeabilization and has been found to significantly increase the uptake and expression of DNA in cells across many organ systems. In addition, it offers a more favorable safety profile compared to other non-viral delivery methods. Studies have shown that microbubble-enhanced sonoporation can elicit significant tissue regeneration in both ectopic and disease models, including bone and vascular tissue regeneration. Despite this, no clinical trials on the use of sonoporation for tissue regeneration have been conducted, although current clinical trials using sonoporation for other indications suggest that the method is safe for use in the clinical setting. In this review, we describe the pre-clinical studies conducted thus far on the use of sonoporation for tissue regeneration. Further, the various techniques used to increase the effectiveness and duration of sonoporation-induced gene transfer, as well as the obstacles that may be currently hindering clinical translation, are explored. Full article

(This article belongs to the Special Issue Stem/Progenitor Cells for Musculoskeletal Disease Modeling and Tissue Repair)

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25 pages, 2299 KiB

Open AccessReview

Exosomes in the Pathogenesis, Progression, and Treatment of Osteoarthritis

by Yishu Fan, Zhong Li and Yuchen He

Bioengineering 2022, 9(3), 99; https://0-doi-org.brum.beds.ac.uk/10.3390/bioengineering9030099 - 27 Feb 2022

Cited by 17 | Viewed by 6411

Abstract

Osteoarthritis (OA) is a prevalent and debilitating age-related joint disease characterized by articular cartilage degeneration, synovial membrane inflammation, osteophyte formation, as well as subchondral bone sclerosis. OA drugs at present are mainly palliative and do not halt or reverse disease progression. Currently, no disease-modifying OA drugs (DMOADs) are available and total joint arthroplasty remains a last resort. Therefore, there is an urgent need for the development of efficacious treatments for OA management. Among all novel pharmaco-therapeutical options, exosome-based therapeutic strategies are highly promising. Exosome cargoes, which include proteins, lipids, cytokines, and various RNA subtypes, are potentially capable of regulating intercellular communications and gene expression in target cells and tissues involved in OA development. With extensive research in recent years, exosomes in OA studies are no longer limited to classic, mesenchymal stem cell (MSC)-derived vesicles. New origins, structures, and functions of exosomes are constantly being discovered and investigated. This review systematically summarizes the non-classic origins, biosynthesis, and extraction of exosomes, describes modification and delivery techniques, explores their role in OA pathogenesis and progression, and discusses their therapeutic potential and hurdles to overcome in OA treatment. Full article

(This article belongs to the Special Issue Stem/Progenitor Cells for Musculoskeletal Disease Modeling and Tissue Repair)

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