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Bioengineering
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Mesenchymal Stem Cells in Tissue Regeneration
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Mesenchymal Stem Cells in Tissue Regeneration

A special issue of Bioengineering (ISSN 2306-5354).

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 44046

Special Issue Editors

Prof. Dr. Dan Simionescu

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Guest Editor
AIMBE Fellow, Department of Bioengineering, Clemson University, Clemson, USA
Interests: regenerative medicine; stem cells; biological scaffolds; bioreactors; biomaterials; biocompatibility
Dr. Christopher DeBorde

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Guest Editor
Department of Bioengineering, Clemson University
Interests: mitral valve tissue engineering
Dr. Agneta Simionescu

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Guest Editor
Department of Bioengineering, Clemson University, Clemson, SC 29634, USA
Interests: cardiovascular tissue engineering in diabetes

Special Issue Information

Dear Colleagues,

Tissue regeneration is slowly becoming a new cornerstone for the medicine of the future. Loosely defined, this field encompasses efforts to integrate the various areas of medical physiology with stem cell biology and engineering for the sole purpose of restoring tissues which otherwise do not have the natural capacity to regenerate.

One major challenge in tissue regeneration is cell sourcing. Among the different options, mesencymal stem cells (MSCs) have been tested in a variety of in vitro, preclinical and clinical scenarios. MSCs are an attractive cell source because they can be readily obtained from patients (autologous) or healthy volunteers (allogenic); in vitro MSCs are easily propagated and manipulated. MSCs have multiple functions, and research into harnessing these capabilities revealed that MSCs are self-propagating cytokine factories also capable of differentiation into a variety of target cells. Despite initial enthusiasm, scientists are still pondering the advantages and limitations of MSCs, use of autologous versus allogenic MSCs, their ability to support tissue regeneration in vitro and in vivo, their true potential for differentiation, their phenotypic stability after differentiation, effectiveness of MSCs collected from patients affected by genetic or metabolic diseases. We also do not understand well enough what kind of scaffolds MSCs actually need, if at all, and what is the effect of synthetic or natural 3D scaffolds on MSC behavior. Thus it is apparent that opportunities for tissue regeneration abound, however in most applications, tissue regeneration is not a “one size fits all” type of therapy.

This is an exciting field which also comes with ample challenges related to the patient’s medical condition and age, metabolic or genetic deficiencies, as well as technical challenges associated with lack of adequate scaffold biomechanics, insufficient vascularity, vulnerability of stem cells, inefficient seeding methods, lack of sophisticated bioreactors and imperfect animal models, among others.

The current Special Issue provides a platform for dissemination and critical evaluation of opportunities and challenges in tissue regeneration using MSCs. It is our belief that your valuable contributions will help advance the field further by providing novel opportunities, approaches and solutions to these challenges.

We are very excited to serve as Guest Editors for this Special Issue and look forward to receiving your manuscripts.

Prof. Dr. Dan Simionescu
Dr. Christopher deBorde
Dr. Agneta Simionescu
Guest Editors

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Published Papers (6 papers)

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Research

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16 pages, 3832 KiB  
Article
Gelatin-Methacryloyl (GelMA) Formulated with Human Platelet Lysate Supports Mesenchymal Stem Cell Proliferation and Differentiation and Enhances the Hydrogel’s Mechanical Properties
by Marline Kirsch, Luise Birnstein, Iliyana Pepelanova, Wiebke Handke, Jessica Rach, Axel Seltsam, Thomas Scheper and Antonina Lavrentieva
Bioengineering 2019, 6(3), 76; https://doi.org/10.3390/bioengineering6030076 - 28 Aug 2019
Cited by 43 | Viewed by 9978
Abstract
Three-dimensional (3D) cell culture is a major focus of current research, since cultivation under physiological conditions provides more reliable information about in vivo cell behavior. 3D cell cultures are used in basic research to better understand intercellular and cell-matrix interactions. Moreover, 3D cell [...] Read more.
Three-dimensional (3D) cell culture is a major focus of current research, since cultivation under physiological conditions provides more reliable information about in vivo cell behavior. 3D cell cultures are used in basic research to better understand intercellular and cell-matrix interactions. Moreover, 3D cell culture plays an increasingly important role in the in vitro testing of bioactive substances and tissue engineering. Gelatin-methacryloyl (GelMA) hydrogels of different degrees of functionalization (DoFs) are a versatile tool for 3D cell culture and related applications such as bioprinting. Human platelet lysate (hPL) has already demonstrated positive effects on 2D cell cultures of different cell types and has proven a valuable alternative to fetal calf serum (FCS). Traditionally, all hydrogels are formulated using buffers. In this study, we supplemented GelMA hydrogels of different DoF with hPL during adipose tissue-derived mesenchymal stem cell (AD-MSCs) encapsulation. We studied the effect of hPL supplementation on the spreading, proliferation, and osteogenic differentiation of AD-MSCs. In addition, the influence of hPL on hydrogel properties was also investigated. We demonstrate that the addition of hPL enhanced AD-MSC spreading, proliferation, and osteogenic differentiation in a concentration-dependent manner. Moreover, the addition of hPL also increased GelMA viscosity and stiffness. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Tissue Regeneration)
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20 pages, 2981 KiB  
Article
Impact of Four Protein Additives in Cryogels on Osteogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells
by Victor Häussling, Sebastian Deninger, Laura Vidoni, Helen Rinderknecht, Marc Ruoß, Christian Arnscheidt, Kiriaki Athanasopulu, Ralf Kemkemer, Andreas K. Nussler and Sabrina Ehnert
Bioengineering 2019, 6(3), 67; https://doi.org/10.3390/bioengineering6030067 - 7 Aug 2019
Cited by 12 | Viewed by 6819
Abstract
Human adipose-derived mesenchymal stem/stromal cells (Ad-MSCs) have great potential for bone tissue engineering. Cryogels, mimicking the three-dimensional structure of spongy bone, represent ideal carriers for these cells. We developed poly(2-hydroxyethyl methacrylate) cryogels, containing hydroxyapatite to mimic inorganic bone matrix. Cryogels were additionally supplemented [...] Read more.
Human adipose-derived mesenchymal stem/stromal cells (Ad-MSCs) have great potential for bone tissue engineering. Cryogels, mimicking the three-dimensional structure of spongy bone, represent ideal carriers for these cells. We developed poly(2-hydroxyethyl methacrylate) cryogels, containing hydroxyapatite to mimic inorganic bone matrix. Cryogels were additionally supplemented with different types of proteins, namely collagen (Coll), platelet-rich plasma (PRP), immune cells-conditioned medium (CM), and RGD peptides (RGD). The different protein components did not affect scaffolds’ porosity or water-uptake capacity, but altered pore size and stiffness. Stiffness was highest in scaffolds with PRP (82.3 kPa), followed by Coll (55.3 kPa), CM (45.6 kPa), and RGD (32.8 kPa). Scaffolds with PRP, CM, and Coll had the largest pore diameters (~60 µm). Ad-MSCs were osteogenically differentiated on these scaffolds for 14 days. Cell attachment and survival rates were comparable for all four scaffolds. Runx2 and osteocalcin levels only increased in Ad-MSCs on Coll, PRP and CM cryogels. Osterix levels increased slightly in Ad-MSCs differentiated on Coll and PRP cryogels. With differentiation alkaline phosphatase activity decreased under all four conditions. In summary, besides Coll cryogel our PRP cryogel constitutes as an especially suitable carrier for bone tissue engineering. This is of special interest, as this scaffold can be generated with patients’ PRP. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Tissue Regeneration)
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9 pages, 2019 KiB  
Article
Human Neonatal Thymus Mesenchymal Stem/Stromal Cells and Chronic Right Ventricle Pressure Overload
by Josue Chery, Shan Huang, Lianghui Gong, Shuyun Wang, Zhize Yuan, Joshua Wong, Jeffrey Lee, Sean Johnson and Ming-Sing Si
Bioengineering 2019, 6(1), 15; https://doi.org/10.3390/bioengineering6010015 - 9 Feb 2019
Cited by 6 | Viewed by 5744
Abstract
Right ventricle (RV) failure secondary to pressure overload is associated with a loss of myocardial capillary density and an increase in oxidative stress. We have previously found that human neonatal thymus mesenchymal stem cells (ntMSCs) promote neovascularization, but the ability of ntMSCs to [...] Read more.
Right ventricle (RV) failure secondary to pressure overload is associated with a loss of myocardial capillary density and an increase in oxidative stress. We have previously found that human neonatal thymus mesenchymal stem cells (ntMSCs) promote neovascularization, but the ability of ntMSCs to express the antioxidant extracellular superoxide dismutase (SOD3) is unknown. We hypothesized that ntMSCs express and secrete SOD3 as well as improve survival in the setting of chronic pressure overload. To evaluate this hypothesis, we compared SOD3 expression in ntMSCs to donor-matched bone-derived MSCs and evaluated the effect of ntMSCs in a rat RV pressure overload model induced by pulmonary artery banding (PAB). The primary outcome was survival, and secondary measures were an echocardiographic assessment of RV size and function as well as histological studies of the RV. We found that ntMSCs expressed SOD3 to a greater degree as compared to bone-derived MSCs. In the PAB model, all ntMSC-treated animals survived to the study endpoint whereas control animals had significantly decreased survival. Treatment animals had significantly less RV fibrosis and increased RV capillary density as compared to controls. We conclude that human ntMSCs demonstrate a therapeutic effect in a model of chronic RV pressure overload, which may in part be due to their antioxidative, antifibrotic, and proangiogenic effects. Given their readily available source, human ntMSCs may be a candidate cell therapy for individuals with congenital heart disease and a pressure-overloaded RV. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Tissue Regeneration)
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13 pages, 3419 KiB  
Article
Analysis of the Intrinsic Self-Organising Properties of Mesenchymal Stromal Cells in Three-Dimensional Co-Culture Models with Endothelial Cells
by Julia Marshall, Amanda Barnes and Paul Genever
Bioengineering 2018, 5(4), 92; https://doi.org/10.3390/bioengineering5040092 - 26 Oct 2018
Cited by 8 | Viewed by 6590
Abstract
Mesenchymal stem/stromal cells (MSCs) are typically characterised by their ability to differentiate into skeletal (osteogenic, chondrogenic and adipogenic) lineages. MSCs also appear to have additional non-stem cell functions in coordinating tissue morphogenesis and organising vascular networks through interactions with endothelial cells (ECs). However, [...] Read more.
Mesenchymal stem/stromal cells (MSCs) are typically characterised by their ability to differentiate into skeletal (osteogenic, chondrogenic and adipogenic) lineages. MSCs also appear to have additional non-stem cell functions in coordinating tissue morphogenesis and organising vascular networks through interactions with endothelial cells (ECs). However, suitable experimental models to examine these apparently unique MSC properties are lacking. Following previous work, we have developed our 3D in vitro co-culture models to enable us to track cellular self-organisation events in heterotypic cell spheroids combining ECs, MSCs and their differentiated progeny. In these systems, MSCs, but not related fibroblastic cell types, promote the assembly of ECs into interconnected networks through intrinsic mechanisms, dependent on the relative abundance of MSC and EC numbers. Perturbation of endogenous platelet-derived growth factor (PDGF) signalling significantly increased EC network length, width and branching. When MSCs were pre-differentiated towards an osteogenic or chondrogenic lineage and co-cultured as mixed 3D spheroids, they segregated into polarised osseous and chondral regions. In the presence of ECs, the pre-differentiated MSCs redistributed to form a central mixed cell core with an outer osseous layer. Our findings demonstrate the intrinsic self-organising properties of MSCs, which may broaden their use in regenerative medicine and advance current approaches. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Tissue Regeneration)
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18 pages, 6424 KiB  
Article
Evaluation of Peripheral Blood and Cord Blood Platelet Lysates in Isolation and Expansion of Multipotent Mesenchymal Stromal Cells
by Ioanna Christou, Panagiotis Mallis, Efstathios Michalopoulos, Theofanis Chatzistamatiou, George Mermelekas, Jerome Zoidakis, Antonia Vlahou and Catherine Stavropoulos-Giokas
Bioengineering 2018, 5(1), 19; https://doi.org/10.3390/bioengineering5010019 - 26 Feb 2018
Cited by 11 | Viewed by 6790
Abstract
Background: Multipotent Mesenchymal Stromal Cells (MSCs) are used in tissue engineering and regenerative medicine. The in vitro isolation and expansion of MSCs involve the use of foetal bovine serum (FBS). However, many concerns have been raised regarding the safety of this product. In [...] Read more.
Background: Multipotent Mesenchymal Stromal Cells (MSCs) are used in tissue engineering and regenerative medicine. The in vitro isolation and expansion of MSCs involve the use of foetal bovine serum (FBS). However, many concerns have been raised regarding the safety of this product. In this study, alternative additives derived either from peripheral or cord blood were tested as an FBS replacement. Methods: Platelet lysates (PL) from peripheral and cord blood were used for the expansion of MSCs. The levels of growth factors in peripheral blood (PB) and cord blood (CB) PLs were determined using the Multiple Reaction Monitoring (MRM). Finally, the cell doubling time (CDT), tri-lineage differentiation and phenotypic characterization of the MSCs expanded with FBS and PLs were determined. Results: MSCs treated with culture media containing FBS and PB-PL, were successfully isolated and expanded, whereas MSCs treated with CB-PL could not be maintained in culture. Furthermore, the MRM analysis yielded differences in growth factor levels between PB-PL and CB-PL. In addition, the MSCs were successfully expanded with FBS and PB-PL and exhibited tri-lineage differentiation and stable phenotypic characteristics. Conclusion: PB-PL could be used as an alternative additive for the production of MSCs culture medium applied to xenogeneic-free expansion and maintenance of MSCs in large scale clinical studies. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Tissue Regeneration)
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Review

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13 pages, 220 KiB  
Review
Augmentation of Dermal Wound Healing by Adipose Tissue-Derived Stromal Cells (ASC)
by Joris A. Van Dongen, Martin C. Harmsen, Berend Van der Lei and Hieronymus P. Stevens
Bioengineering 2018, 5(4), 91; https://doi.org/10.3390/bioengineering5040091 - 26 Oct 2018
Cited by 37 | Viewed by 6830
Abstract
The skin is the largest organ of the human body and is the first line of defense against physical and biological damage. Thus, the skin is equipped to self-repair and regenerates after trauma. Skin regeneration after damage comprises a tightly spatial-temporally regulated process [...] Read more.
The skin is the largest organ of the human body and is the first line of defense against physical and biological damage. Thus, the skin is equipped to self-repair and regenerates after trauma. Skin regeneration after damage comprises a tightly spatial-temporally regulated process of wound healing that involves virtually all cell types in the skin. Wound healing features five partially overlapping stages: homeostasis, inflammation, proliferation, re-epithelization, and finally resolution or fibrosis. Dysreguled wound healing may resolve in dermal scarring. Adipose tissue is long known for its suppressive influence on dermal scarring. Cultured adipose tissue-derived stromal cells (ASCs) secrete a plethora of regenerative growth factors and immune mediators that influence processes during wound healing e.g., angiogenesis, modulation of inflammation and extracellular matrix remodeling. In clinical practice, ASCs are usually administered as part of fractionated adipose tissue i.e., as part of enzymatically isolated SVF (cellular SVF), mechanically isolated SVF (tissue SVF), or as lipograft. Enzymatic isolation of SVF obtained adipose tissue results in suspension of adipocyte-free cells (cSVF) that lack intact intercellular adhesions or connections to extracellular matrix (ECM). Mechanical isolation of SVF from adipose tissue destructs the parenchyma (adipocytes), which results in a tissue SVF (tSVF) with intact connections between cells, as well as matrix. To date, due to a lack of well-designed prospective randomized clinical trials, neither cSVF, tSVF, whole adipose tissue, or cultured ASCs can be indicated as the preferred preparation procedure prior to therapeutic administration. In this review, we present and discuss current literature regarding the different administration options to apply ASCs (i.e., cultured ASCs, cSVF, tSVF, and lipografting) to augment dermal wound healing, as well as the available indications for clinical efficacy. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells in Tissue Regeneration)
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