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Mesenchymal Stem/Progenitor Cells and Their Derivates in Tissue Regeneration - Part II

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

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 14160

Special Issue Editor

Prof. Dr. Aleksandra Klimczak

E-Mail Website
Guest Editor
The Laboratory of Biology of Stem and Neoplastic Cells, Hirszfeld Institute of Immunology and Experimental Therapy PAS, Wroclaw, Poland
Interests: mesenchymal stem cells (MSCs); MSCs secretome; microvesicles (MVs); MSCs and bioactive factors; regenerative medicine; cellular therapy; muscular dystrophy; wound healing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The first Special Issue “Mesenchymal Stem/Progenitor Cells and Their Derivates in Tissue Regeneration” has been recognized by many scientific groups and was a successful endeavor. This encouraged us to continue this Special Issue with a second part devoted to research concerning mesenchymal stem cell application in regenerative medicine.

Mesenchymal stem/progenitor cells (MSCs) reside in many human tissues and organs and play important roles in tissue regeneration and tissue homeostasis. These cells can be isolated from different tissues in the adult human body, expanded in vitro and applied for the regeneration of tissues and organs damaged by age, disease or extensive injury. Cells bearing MSC characteristics differ in the facets of proliferation and differentiation, which results in their diverse biological potential and applications in tissue regeneration. Experimental studies have shown that not only MSCs, but also their derivates—such as a conditioned medium containing a variety of bioactive factors or extracellular vesicles (EVs) (microvesicles and exosomes) carrying various cytoplasmic components, including lipids, DNA fragments and RNA (including mRNA and microRNA)—contribute to tissue recovery and angiogenesis and modify the inflammatory microenvironment in a paracrine and endocrine manner. This Special Issue will present state-of-the-art studies concerning the therapeutic effects of various stem/progenitor cells and/or their derivates in the context of tissue and organ regeneration. The potential topics to be covered include (1) bioactive factors released by mesenchymal stem/progenitor cells for cell-free therapy in tissue regeneration, (2) extracellular vesicles from parental mesenchymal stem/progenitor cells for cell-free therapy in tissue regeneration and (3) the proangiogenic properties of bioactive factors and/or extracellular vesicles released by MSCs.

Prof. Dr. Aleksandra Klimczak
Guest Editor

Manuscript Submission Information

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Keywords

  • mesenchymal stem cells
  • mesenchymal stem/progenitor cells
  • MSC secretome
  • bioactive factors released by MSCs
  • MSC extracellular vesicles (EVs)
  • cell-free therapy
  • tissue regeneration
  • MSCs secretome and angiogenesis

Published Papers (7 papers)

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Research

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20 pages, 9081 KiB  
Article
Osteogenic Potential of Human Dental Pulp Stem Cells (hDPSCs) Growing on Poly L-Lactide-Co-Caprolactone and Hyaluronic Acid (HYAFF-11TM) Scaffolds
by Julia K. Bar, Anna Lis-Nawara, Tomasz Kowalczyk, Piotr G. Grelewski, Sandra Stamnitz, Hanna Gerber and Aleksandra Klimczak
Int. J. Mol. Sci. 2023, 24(23), 16747; https://doi.org/10.3390/ijms242316747 - 25 Nov 2023
Viewed by 700
Abstract
Bone tissue engineering using different scaffolds is a new therapeutic approach in regenerative medicine. This study explored the osteogenic potential of human dental pulp stem cells (hDPSCs) grown on a hydrolytically modified poly(L-lactide-co-caprolactone) (PLCL) electrospun scaffold and a non-woven hyaluronic acid (HYAFF-11™) mesh. [...] Read more.
Bone tissue engineering using different scaffolds is a new therapeutic approach in regenerative medicine. This study explored the osteogenic potential of human dental pulp stem cells (hDPSCs) grown on a hydrolytically modified poly(L-lactide-co-caprolactone) (PLCL) electrospun scaffold and a non-woven hyaluronic acid (HYAFF-11™) mesh. The adhesion, immunophenotype, and osteogenic differentiation of hDPSCs seeded on PLCL and HYAFF-11™ scaffolds were analyzed. The results showed that PLCL and HYAFF-11™ scaffolds significantly supported hDPSCs adhesion; however, hDPSCs’ adhesion rate was significantly higher on PLCL than on HYAFF-11™. SEM analysis confirmed good adhesion of hDPSCs on both scaffolds before and after osteogenesis. Alizarin red S staining showed mineral deposits on both scaffolds after hDPSCs osteogenesis. The mRNA levels of runt-related transcription factor 2 (Runx2), collagen type I (Coll-I), osterix (Osx), osteocalcin (Ocn), osteopontin (Opn), bone sialoprotein (Bsp), and dentin sialophosphoprotein (Dspp) gene expression and their proteins were higher in hDPSCs after osteogenic differentiation on both scaffolds compared to undifferentiated hDPSCs on PLCL and HYAFF-11™. These results showed that PLCL scaffolds provide a better environment that supports hDPSCs attachment and osteogenic differentiation than HYAFF-11™. The high mRNA of early osteogenic gene expression and mineral deposits observed after hDPSCs osteogenesis on a PLCL mat indicated its better impact on hDPSCs’ osteogenic potential than that of HYAFF-11™, and hDPSC/PLCL constructs might be considered in the future as an innovative approach to bone defect repair. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Progenitor Cells and Their Derivates in Tissue Regeneration - Part II)
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23 pages, 3468 KiB  
Article
Mesenchymal Stem Cell Conditioned Medium Modulates Inflammation in Tenocytes: Complete Conditioned Medium Has Superior Therapeutic Efficacy than Its Extracellular Vesicle Fraction
by Robert Soukup, Iris Gerner, Thomas Mohr, Sinan Gueltekin, Johannes Grillari and Florien Jenner
Int. J. Mol. Sci. 2023, 24(13), 10857; https://doi.org/10.3390/ijms241310857 - 29 Jun 2023
Cited by 1 | Viewed by 1450
Abstract
Tendinopathy, a prevalent overuse injury, lacks effective treatment options, leading to a significant impact on quality of life and socioeconomic burden. Mesenchymal stem/stromal cells (MSCs) and their secretome, including conditioned medium (CM) and extracellular vesicles (EVs), have shown promise in tissue regeneration and [...] Read more.
Tendinopathy, a prevalent overuse injury, lacks effective treatment options, leading to a significant impact on quality of life and socioeconomic burden. Mesenchymal stem/stromal cells (MSCs) and their secretome, including conditioned medium (CM) and extracellular vesicles (EVs), have shown promise in tissue regeneration and immunomodulation. However, it remains unclear which components of the secretome contribute to their therapeutic effects. This study aimed to compare the efficacy of CM, EVs, and the soluble protein fraction (PF) in treating inflamed tenocytes. CM exhibited the highest protein and particle concentrations, followed by PF and EVs. Inflammation significantly altered gene expression in tenocytes, with CM showing the most distinct separation from the inflamed control group. Treatment with CM resulted in the most significant differential gene expression, with both upregulated and downregulated genes related to inflammation and tissue regeneration. EV treatment also demonstrated a therapeutic effect, albeit to a lesser extent. These findings suggest that CM holds superior therapeutic efficacy compared with its EV fraction alone, emphasizing the importance of the complete secretome in tendon injury treatment. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Progenitor Cells and Their Derivates in Tissue Regeneration - Part II)
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18 pages, 7978 KiB  
Article
Evaluation of Changes in Some Functional Properties of Human Mesenchymal Stromal Cells Induced by Low Doses of Ionizing Radiation
by Daria Yu. Usupzhanova, Tatiana A. Astrelina, Irina V. Kobzeva, Yulia B. Suchkova, Vitaliy A. Brunchukov, Anna A. Rastorgueva, Victoria A. Nikitina and Alexander S. Samoilov
Int. J. Mol. Sci. 2023, 24(7), 6346; https://doi.org/10.3390/ijms24076346 - 28 Mar 2023
Viewed by 1006
Abstract
Each person is inevitably exposed to low doses of ionizing radiation (LDIR) throughout their life. The research results of LDIR effects are ambiguous and an accurate assessment of the risks associated with the influence of LDIR is an important task. Mesenchymal stromal cells [...] Read more.
Each person is inevitably exposed to low doses of ionizing radiation (LDIR) throughout their life. The research results of LDIR effects are ambiguous and an accurate assessment of the risks associated with the influence of LDIR is an important task. Mesenchymal stromal cells (MSCs) are the regenerative reserve of an adult organism; because of this, they are a promising model for studying the effects of LDIR. The qualitative and quantitative changes in their characteristics can also be considered promising criteria for assessing the risks of LDIR exposure. The MSCs from human connective gingiva tissue (hG-MSCs) were irradiated at doses of 50, 100, 250, and 1000 mGy by the X-ray unit RUST-M1 (Russia). The cells were cultured continuously for 64 days after irradiation. During the study, we evaluated the secretory profile of hG-MSCs (IL-10, IDO, IL-6, IL-8, VEGF-A) using an ELISA test, the immunophenotype (CD45, CD34, CD90, CD105, CD73, HLA-DR, CD44) using flow cytometry, and the proliferative activity using the xCelligence RTCA cell analyzer at the chosen time points. The results of study have indicated the development of stimulating effects in the early stages of cultivation after irradiation using low doses of X-ray radiation. On the contrary, the effects of the low doses were comparable with the effects of medium doses of X-ray radiation in the long-term periods of cultivation after irradiation and have indicated the inhibition of the functional activity of MSCs. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Progenitor Cells and Their Derivates in Tissue Regeneration - Part II)
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22 pages, 5710 KiB  
Article
Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria?
by Ljubava D. Zorova, Sergei I. Kovalchuk, Vasily A. Popkov, Valery P. Chernikov, Anastasia A. Zharikova, Anastasia A. Khutornenko, Savva D. Zorov, Konstantin S. Plokhikh, Roman A. Zinovkin, Ekaterina A. Evtushenko, Valentina A. Babenko, Irina B. Pevzner, Yulia A. Shevtsova, Kirill V. Goryunov, Egor Y. Plotnikov, Denis N. Silachev, Gennady T. Sukhikh and Dmitry B. Zorov
Int. J. Mol. Sci. 2022, 23(13), 7408; https://doi.org/10.3390/ijms23137408 - 03 Jul 2022
Cited by 20 | Viewed by 3180
Abstract
Extracellular vesicles (EV) derived from stem cells have become an effective complement to the use in cell therapy of stem cells themselves, which has led to an explosion of research into the mechanisms of vesicle formation and their action. There is evidence demonstrating [...] Read more.
Extracellular vesicles (EV) derived from stem cells have become an effective complement to the use in cell therapy of stem cells themselves, which has led to an explosion of research into the mechanisms of vesicle formation and their action. There is evidence demonstrating the presence of mitochondrial components in EV, but a definitive conclusion about whether EV contains fully functional mitochondria has not yet been made. In this study, two EV fractions derived from mesenchymal stromal stem cells (MSC) and separated by their size were examined. Flow cytometry revealed the presence of mitochondrial lipid components capable of interacting with mitochondrial dyes MitoTracker Green and 10-nonylacridine orange; however, the EV response to the probe for mitochondrial membrane potential was negative. Detailed analysis revealed components from all mitochondria compartments, including house-keeping mitochondria proteins and DNA as well as energy-related proteins such as membrane-localized proteins of complexes I, IV, and V, and soluble proteins from the Krebs cycle. When assessing the functional activity of mitochondria, high variability in oxygen consumption was noted, which was only partially attributed to mitochondrial respiratory activity. Our findings demonstrate that the EV contain all parts of mitochondria; however, their independent functionality inside EV has not been confirmed, which may be due either to the absence of necessary cofactors and/or the EV formation process and, probably the methodology of obtaining EV. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Progenitor Cells and Their Derivates in Tissue Regeneration - Part II)
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Review

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15 pages, 1642 KiB  
Review
Towards the Standardization of Mesenchymal Stem Cell Secretome-Derived Product Manufacturing for Tissue Regeneration
by Batoul Chouaib, Mandana Haack-Sørensen, Franck Chaubron, Frederic Cuisinier and Pierre-Yves Collart-Dutilleul
Int. J. Mol. Sci. 2023, 24(16), 12594; https://doi.org/10.3390/ijms241612594 - 09 Aug 2023
Cited by 4 | Viewed by 2040
Abstract
Mesenchymal stem cell secretome or conditioned medium (MSC-CM) is a combination of biomolecules and growth factors in cell culture growth medium, secreted by mesenchymal stem cells (MSCs), and the starting point of several derived products. MSC-CM and its derivatives could be applied after [...] Read more.
Mesenchymal stem cell secretome or conditioned medium (MSC-CM) is a combination of biomolecules and growth factors in cell culture growth medium, secreted by mesenchymal stem cells (MSCs), and the starting point of several derived products. MSC-CM and its derivatives could be applied after injuries and could mediate most of the beneficial regenerative effects of MSCs without the possible side effects of using MSCs themselves. However, before the clinical application of these promising biopharmaceuticals, several issues such as manufacturing protocols and quality control must be addressed. This review aims to underline the influence of the procedure for conditioned medium production on the quality of the secretome and its derivatives and highlights the questions considering cell sources and donors, cell expansion, cell passage number and confluency, conditioning period, cell culture medium, microenvironment cues, and secretome-derived product purification. A high degree of variability in MSC secretomes is revealed based on these parameters, confirming the need to standardize and optimize protocols. Understanding how bioprocessing and manufacturing conditions interact to determine the quantity, quality, and profile of MSC-CM is essential to the development of good manufacturing practice (GMP)-compliant procedures suitable for replacing mesenchymal stem cells in regenerative medicine. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Progenitor Cells and Their Derivates in Tissue Regeneration - Part II)
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12 pages, 687 KiB  
Review
Potency Assays for Mesenchymal Stromal Cell Secretome-Based Products for Tissue Regeneration
by Georgy Sagaradze, Anna Monakova and Anastasia Efimenko
Int. J. Mol. Sci. 2023, 24(11), 9379; https://doi.org/10.3390/ijms24119379 - 27 May 2023
Viewed by 1900
Abstract
Adult stem cells maintaining tissue homeostasis and regeneration are tightly regulated by their specific microenvironments or stem cell niches. The dysfunction of niche components may alter the activity of stem cells and ultimately lead to intractable chronic or acute disorders. To overcome this [...] Read more.
Adult stem cells maintaining tissue homeostasis and regeneration are tightly regulated by their specific microenvironments or stem cell niches. The dysfunction of niche components may alter the activity of stem cells and ultimately lead to intractable chronic or acute disorders. To overcome this dysfunction, niche-targeting regenerative medicine treatments such as gene, cell, and tissue therapy are actively investigated. Here, multipotent mesenchymal stromal cells (MSCs), and particularly their secretomes, are of high interest due to their potency to recover and reactivate damaged or lost stem cell niches. However, a workflow for the development of MSC secretome-based products is not fully covered by regulatory authorities, and and this issue significantly complicates their clinical translation and has possibly been expressed in a huge number of failed clinical trials. One of the most critical issues in this regard relates to the development of potency assays. In this review, guidelines for biologicals and cell therapies are considered to be applied for the development of potency assays for the MSC secretome-based products that aim for tissue regeneration. Specific attention is paid to their possible effects on stem cell niches and to a spermatogonial stem cell niche in particular. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Progenitor Cells and Their Derivates in Tissue Regeneration - Part II)
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15 pages, 1140 KiB  
Review
Intraarticular Injections of Mesenchymal Stem Cells in Knee Osteoarthritis: A Review of Their Current Molecular Mechanisms of Action and Their Efficacy
by Emérito Carlos Rodríguez-Merchán
Int. J. Mol. Sci. 2022, 23(23), 14953; https://doi.org/10.3390/ijms232314953 - 29 Nov 2022
Cited by 5 | Viewed by 3233
Abstract
More than 10% of the world’s population suffers from osteoarthritis (OA) of the knee, with a lifetime risk of 45%. Current treatments for knee OA pain are as follows: weight control; oral pharmacological treatment (non-steroidal anti-inflammatory drugs, paracetamol, opioids); mechanical aids (crutches, walkers, [...] Read more.
More than 10% of the world’s population suffers from osteoarthritis (OA) of the knee, with a lifetime risk of 45%. Current treatments for knee OA pain are as follows: weight control; oral pharmacological treatment (non-steroidal anti-inflammatory drugs, paracetamol, opioids); mechanical aids (crutches, walkers, braces, orthotics); therapeutic physical exercise; and intraarticular injections of corticosteroids, hyaluronic acid, and platelet-rich plasma (PRP). The problem is that such treatments usually relieve joint pain for only a short period of time. With respect to intraarticular injections, corticosteroids relieve pain for several weeks, while hyaluronic acid and PRP relieve pain for several months. When the above treatments fail to control knee pain, total knee arthroplasty (TKA) is usually indicated; however, although a very effective surgical technique, it can be associated with medical and postoperative (surgery-related) complications. Therefore, it seems essential to look for safe and effective alternative treatments to TKA. Recently, there has been much research on intraarticular injections of mesenchymal stem cells (MSCs) for the management of OA of the knee joint. This article reviews the latest information on the molecular mechanisms of action of MSCs and their potential therapeutic benefit in clinical practice in patients with painful knee OA. Although most recent publications claim that intraarticular injections of MSCs relieve joint pain in the short term, their efficacy remains controversial given that the existing scientific information on MSCs is indecisive. Before recommending intraarticular MSCs injections routinely in patients with painful knee OA, more studies comparing MSCs with placebo are needed. Furthermore, a standard protocol for intraarticular injections of MSCs in knee OA is needed. Full article
(This article belongs to the Special Issue Mesenchymal Stem/Progenitor Cells and Their Derivates in Tissue Regeneration - Part II)
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