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New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 24121

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Prof. Dr. Sung-Chul Jung

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Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
Interests: cell therapy; differentiation; muscle; lysosomal storage disease; Schwann cells; peripheral neuropathy; mesenchymal stem cells
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Special Issue Information

Dear Colleagues,

Mesenchymal stem cells (MSCs) are multipotent cells derived from various tissues including bone marrow and adipose tissues. MSCs have the capacity to differentiate into mesodermal lineages, including chondroblasts, osteoblasts, and adiocytes. Recently, novel tissue sources and various differentiation capacities of MSCs have been reported. However, progress in the clinical application and therapeutic use of MSCs is limited and further behind than expected. In the case of cell therapy using differentiated cells, the optimization of the quality of cell therapy candidates is very difficult. In addition to MSCs themselves, the importance of the characterization and therapeutic use of extracellular vesicles derived from MSCs has increased. This Special Issue will include studies on novel tissue sources for MSCs, the differentiation potential of MSCs derived from various sources, optimization of the quality of MSCs, including cells differentiated from MSCs, and other therapeutic candidates derived from MSCs, such as extracellular vesicles and MSC spheroids. In the case of therapeutic applications, the molecular characteristics of nondifferentiated/differentiated MSCs and their mode of action for clinical efficacy will be described.

Prof. Dr. Sung-Chul Jung
Guest Editor

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Keywords

Mesenchymal stem cells
Tissues
Novel sources
Differentiation
Quality control
Optimization
Extracellular vesicles
Secretome
Spheroids
Therapeutics

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Published Papers (9 papers)

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Editorial

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4 pages, 205 KiB

Open AccessEditorial

New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells 2.0

by Sung-Chul Jung and Saeyoung Park

Int. J. Mol. Sci. 2023, 24(4), 3938; https://doi.org/10.3390/ijms24043938 - 15 Feb 2023

Cited by 4 | Viewed by 1574

Abstract

For the clinical application of mesenchymal stem cells (MSCs), the optimization of biological products (e [...] Full article

(This article belongs to the Special Issue New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells 2.0)

Research

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14 pages, 3035 KiB

Open AccessArticle

Decellularization of Human Pancreatic Fragments with Pronounced Signs of Structural Changes

by Victor I. Sevastianov, Anna S. Ponomareva, Natalia V. Baranova, Lyudmila A. Kirsanova, Yulia B. Basok, Evgeniy A. Nemets, Dmitry N. Kruglov, Igor A. Miloserdov and Sergey V. Gautier

Int. J. Mol. Sci. 2023, 24(1), 119; https://doi.org/10.3390/ijms24010119 - 21 Dec 2022

Cited by 7 | Viewed by 1830

Abstract

A significant lack of donor organs restricts the opportunity to obtain tissue-specific scaffolds for tissue-engineering technologies. One of the acceptable solutions is the development of decellularization protocols for a human donor pancreas unsuitable for transplantation. A protocol of obtaining a biocompatible tissue-specific scaffold from decellularized fragments with pronounced human pancreas lipomatosis signs with preserved basic fibrillary proteins of a pancreatic tissue extracellular matrix was developed. The scaffold supports the adhesion and proliferation of human adipose derived stem cell (hADSCs) and prolongs the viability and insulin-producing function of pancreatic islets. Experiments conducted allow for the reliance on the prospects of using the donor pancreas unsuitable for transplantation in the technologies of tissue engineering and regenerative medicine, including the development of a tissue equivalent of a pancreas. Full article

(This article belongs to the Special Issue New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells 2.0)

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21 pages, 11175 KiB

Open AccessArticle

Effects of Different Basal Cell Culture Media upon the Osteogenic Response of hMSCs Evaluated by ^99mTc-HDP Labeling

by Tobias Grossner, Uwe Haberkorn, Jakob Hofmann and Tobias Gotterbarm

Int. J. Mol. Sci. 2022, 23(11), 6288; https://doi.org/10.3390/ijms23116288 - 3 Jun 2022

Cited by 7 | Viewed by 2347

Abstract

The osteogenic differentiation of mesenchymal stem cells is now a standard procedure in modern bone tissue engineering. As this is a promising field for future clinical applications, many cell culture media exist to promote osteogenic differentiation. Prior to differentiation, cells must be expanded to obtain sufficient numbers for experiments. Little evidence is available regarding the optimal media combination for expansion and differentiation to maximize the osteogenic response. Therefore, human BM-MSCs (n = 6) were expanded in parallel in DMEM (Dulbecco’s Modified Eagle Medium) LG (Low Glucose) and α-MEM (Minimum Essential Media alpha-modification), followed by simultaneous monolayer differentiation toward the osteogenic lineage in: 1. DMEM LG (Low Glucose), 2. DMEM HG (High Glucose), 3. α-MEM, 4. “Bernese medium”, and 5. “Verfaillie medium”, with a corresponding negative control (total 20 groups). As a marker for osteogenic differentiation, hydroxyapatite was accessed using radioactive ^99mTc-HDP labeling and quantitative alizarin red staining. The results indicate that all media except “Bernese medium” are suitable for osteogenic differentiation, while there was evidence that DMEM LG is partly superior when used for expansion and differentiation of BM-hMSCs. Using “Verfaillie medium” after DMEM LG expansion led to the highest grade of osteogenic differentiation. Nevertheless, the difference was not significant. Therefore, we recommend using DMEM LG for robust osteogenic differentiation, as it is highly suitable for that purpose, economical compared to other media, and requires little preparation time. Full article

(This article belongs to the Special Issue New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells 2.0)

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14 pages, 3005 KiB

Open AccessArticle

TGFβ-Treated Placenta-Derived Mesenchymal Stem Cells Selectively Promote Anti-Adipogenesis in Thyroid-Associated Ophthalmopathy

by Hyun-Ah Shin, Mira Park, Jasvinder Paul Banga and Helen Lew

Int. J. Mol. Sci. 2022, 23(10), 5603; https://doi.org/10.3390/ijms23105603 - 17 May 2022

Cited by 5 | Viewed by 2240

Abstract

Orbital fibroblasts (OFs) in thyroid-associated ophthalmopathy (TAO) are differentiated from pre-adipocytes and mature adipocytes; increased lipid and fat expansion are the major characteristics of ophthalmic manifestations. Human placental mesenchymal stem cells (hPMSCs) were reported to immunomodulate pathogenesis and suppress adipogenesis in TAO OFs. Here, we prepared transforming growth factor β (TGFβ, 20 ng/mL)-treated hPMSCs (TGFβ-hPMSCs) in order to enhance anti-adipogenic effects in vitro and in TAO mice. TAO OFs were grown in a differentiation medium and then co-cultured with hPMSCs or TGFβ-hPMSCs. TAO OFs were analyzed via quantitative real-time polymerase chain reaction, Oil red O staining, and western blotting. The results showed that TGFβ-hPMSCs reduced the expression of adipogenic, lipogenic, and fibrotic genes better than hPMSCs in TAO OFs. Moreover, the adipose area decreased more in TAO mice injected with TGFβ-hPMSCs compared to those injected with hPMSCs or a steroid. Further, TGFβ-hPMSCs inhibited inflammation as effectively as a steroid. In conclusion, TGFβ-hPMSCs suppressed adipogenesis and lipogenesis in vitro and in TAO mice, and the effects were mediated by the SMAD 2/3 pathways. Furthermore, TGFβ-hPMSCs exhibited anti-inflammatory and anti-fibrotic functions, which suggests that they could be a new and safe method to promote the anti-adipogenic function of hPMSCs to treat TAO patients. Full article

(This article belongs to the Special Issue New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells 2.0)

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12 pages, 2345 KiB

Open AccessArticle

Thrombin Preconditioning Improves the Therapeutic Efficacy of Mesenchymal Stem Cells in Severe Intraventricular Hemorrhage Induced Neonatal Rats

by So Yeon Jung, Young Eun Kim, Won Soon Park, So Yoon Ahn, Dong Kyung Sung, Se In Sung, Kyeung Min Joo, Seong Gi Kim and Yun Sil Chang

Int. J. Mol. Sci. 2022, 23(8), 4447; https://doi.org/10.3390/ijms23084447 - 18 Apr 2022

Cited by 13 | Viewed by 2718

Abstract

Severe intraventricular hemorrhage (IVH) remains a major cause of high mortality and morbidity in extremely preterm infants. Mesenchymal stem cell (MSC) transplantation is a possible therapeutic option, and development of therapeutics with enhanced efficacy is necessary. This study investigated whether thrombin preconditioning improves the therapeutic efficacy of human Wharton’s jelly-derived MSC transplantation for severe neonatal IVH, using a rat model. Severe neonatal IVH was induced by injecting 150 μL blood into each lateral ventricle on postnatal day (P) 4 in Sprague-Dawley rats. After 2 days (P6), naïve MSCs or thrombin-preconditioned MSCs (1 × 10⁵/10 μL) were transplanted intraventricularly. After behavioral tests, brain tissues and cerebrospinal fluid of P35 rats were obtained for histological and biochemical analyses, respectively. Thrombin-preconditioned MSC transplantation significantly reduced IVH-induced ventricular dilatation on in vivo magnetic resonance imaging, which was coincident with attenuations of reactive gliosis, cell death, and the number of activated microglia and levels of inflammatory cytokines after IVH induction, compared to naïve MSC transplantation. In the behavioral tests, the sensorimotor and memory functions significantly improved after transplantation of thrombin-preconditioned MSCs, compared to naïve MSCs. Overall, thrombin preconditioning significantly improves the therapeutic potential and more effectively attenuates brain injury, including progressive ventricular dilatation, gliosis, cell death, inflammation, and neurobehavioral functional impairment, in newborn rats with induced severe IVH than does naïve MSC transplantation. Full article

(This article belongs to the Special Issue New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells 2.0)

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24 pages, 5795 KiB

Open AccessArticle

Autophagy Signaling by Neural-Induced Human Adipose Tissue-Derived Stem Cell-Conditioned Medium during Rotenone-Induced Toxicity in SH-SY5Y Cells

by Mahesh Ramalingam, Han-Seong Jeong, Jinsu Hwang, Hyong-Ho Cho, Byeong C. Kim, Eungpil Kim and Sujeong Jang

Int. J. Mol. Sci. 2022, 23(8), 4193; https://doi.org/10.3390/ijms23084193 - 10 Apr 2022

Cited by 14 | Viewed by 3506

Abstract

Rotenone (ROT) inhibits mitochondrial complex I, leading to reactive oxygen species formation, which causes neurodegeneration and alpha-synuclein (α-syn) aggregation and, consequently, Parkinson’s disease. We previously found that a neurogenic differentiated human adipose tissue-derived stem cell-conditioned medium (NI-hADSC-CM) was protective against ROT-induced toxicity in SH-SY5Y cells. In the present study, ROT significantly decreased the phospho (p)-mTORC1/total (t)-mTOR, p-mTORC2/t-mTOR, and p-/t-ULK1 ratios and the ATG13 level by increasing the DEPTOR level and p-/t-AMPK ratio. Moreover, ROT increased the p-/t-Akt ratio and glycogen synthase kinase-3β (GSK3β) activity by decreasing the p-/t-ERK1/2 ratios and beclin-1 level. ROT also promoted the lipidation of LC3B-I to LC3B-II by inducing autophagosome formation in Triton X-100-soluble and -insoluble cell lysate fractions. Additionally, the levels of ATG3, 5, 7, and 12 were decreased, along with those of lysosomal LAMP1, LAMP2, and TFEB, leading to lysosomal dysfunction. However, NI-hADSC-CM treatment increased the p-mTORC1, p-mTORC2, p-ULK1, p-Akt, p-ERK1/2, ATG13, and beclin-1 levels and decreased the p-AMPK level and GSK3β activity in response to ROT-induced toxicity. Additionally, NI-hADSC-CM restored the LC3B-I level, increased the p62 level, and normalized the ATG and lysosomal protein amounts to control levels. Autophagy array revealed that the secreted proteins in NI-hADSC-CM could be crucial in the neuroprotection. Taken together, our results showed that the neuroprotective effects of NI-hADSC-CM on the autophagy signaling pathways could alleviate the aggregation of α-syn in Parkinson’s disease and other neurodegenerative disorders. Full article

(This article belongs to the Special Issue New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells 2.0)

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21 pages, 5945 KiB

Open AccessArticle

Knee and Peri-Knee Tissues of Post Mortem Donors Are Strategic Sources of Mesenchymal Stem/Stromal Cells for Regenerative Procedures

by Gregor Haring and Janja Zupan

Int. J. Mol. Sci. 2022, 23(6), 3170; https://doi.org/10.3390/ijms23063170 - 15 Mar 2022

Cited by 4 | Viewed by 2233

Abstract

Tissues of post mortem donors represent valuable alternative sources for the isolation of primary cells with mesenchymal stem/stromal cell (MSC)-like properties. However, the properties of primary cells derived from different tissues and at different post mortem times are poorly recognized. Here, we aim to identify the optimal tissue source between three knee and peri-knee tissues for the isolation of primary cells with MSC-like properties, and to define the influence of the time post mortem on the properties of these cells. We harvested tissues from subchondral bone marrow, synovium and periosteum from 32 donors at various post mortem times. Primary cells were evaluated using detailed in vitro analyses, including colony formation, trilineage differentiation, immunophenotyping and skeletal stem cell marker-gene expression profiling. These data show that the primary cells with MSC-like properties isolated from these three tissues show no differences in their properties, except for higher expression of CD146 in bone-marrow cells. The success rate of the primary cell isolation is dependent on the post mortem time. However, synovium and periosteum cells isolated more than 48 h post mortem show improved osteogenic and chondrogenic potential. This study suggests that knee and peri-knee tissues from donors even 3 days post mortem are strategic sources of MSCs for regenerative procedures. Full article

(This article belongs to the Special Issue New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells 2.0)

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16 pages, 2386 KiB

Open AccessArticle

Density-Dependent Differentiation of Tonsil-Derived Mesenchymal Stem Cells into Parathyroid-Hormone-Releasing Cells

by Ji Yeon Kim, Saeyoung Park, Se-Young Oh, Yu Hwa Nam, Young Min Choi, Yeonzi Choi, Ha Yeong Kim, Soo Yeon Jung, Han Su Kim, Inho Jo and Sung-Chul Jung

Int. J. Mol. Sci. 2022, 23(2), 715; https://doi.org/10.3390/ijms23020715 - 10 Jan 2022

Cited by 5 | Viewed by 2390

Abstract

Mesenchymal stem cells (MSCs) can differentiate into endoderm lineages, especially parathyroid-hormone (PTH)-releasing cells. We have previously reported that tonsil-derived MSC (T-MSC) can differentiate into PTH-releasing cells (T-MSC-PTHCs), which restored the parathyroid functions in parathyroidectomy (PTX) rats. In this study, we demonstrate quality optimization by standardizing the differentiation rate for a better clinical application of T-MSC-PTHCs to overcome donor-dependent variation of T-MSCs. Quantitation results of PTH mRNA copy number in the differentiated cells and the PTH concentration in the conditioned medium confirmed that the differentiation efficiency largely varied depending on the cells from each donor. In addition, the differentiation rate of the cells from all the donors greatly improved when differentiation was started at a high cell density (100% confluence). The large-scale expression profiling of T-MSC-PTHCs by RNA sequencing indicated that those genes involved in exiting the differentiation and the cell cycle were the major pathways for the differentiation of T-MSC-PTHCs. Furthermore, the implantation of the T-MSC-PTHCs, which were differentiated at a high cell density embedded in hyaluronic acid, resulted in a higher serum PTH in the PTX model. This standardized efficiency of differentiation into PTHC was achieved by initiating differentiation at a high cell density. Our findings provide a potential solution to overcome the limitations due to donor-dependent variation by establishing a standardized differentiation protocol for the clinical application of T-MSC therapy in treating hypoparathyroidism. Full article

(This article belongs to the Special Issue New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells 2.0)

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Review

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21 pages, 1285 KiB

Open AccessReview

Connection between Mesenchymal Stem Cells Therapy and Osteoclasts in Osteoarthritis

by Lidia Ibáñez, Paloma Guillem-Llobat, Marta Marín and María Isabel Guillén

Int. J. Mol. Sci. 2022, 23(9), 4693; https://doi.org/10.3390/ijms23094693 - 23 Apr 2022

Cited by 14 | Viewed by 4066

Abstract

The use of mesenchymal stem cells constitutes a promising therapeutic approach, as it has shown beneficial effects in different pathologies. Numerous in vitro, pre-clinical, and, to a lesser extent, clinical trials have been published for osteoarthritis. Osteoarthritis is a type of arthritis that affects diarthritic joints in which the most common and studied effect is cartilage degradation. Nowadays, it is known that osteoarthritis is a disease with a very powerful inflammatory component that affects the subchondral bone and the rest of the tissues that make up the joint. This inflammatory component may induce the differentiation of osteoclasts, the bone-resorbing cells. Subchondral bone degradation has been suggested as a key process in the pathogenesis of osteoarthritis. However, very few published studies directly focus on the activity of mesenchymal stem cells on osteoclasts, contrary to what happens with other cell types of the joint, such as chondrocytes, synoviocytes, and osteoblasts. In this review, we try to gather the published bibliography in relation to the effects of mesenchymal stem cells on osteoclastogenesis. Although we find promising results, we point out the need for further studies that can support mesenchymal stem cells as a therapeutic tool for osteoclasts and their consequences on the osteoarthritic joint. Full article

(This article belongs to the Special Issue New Sources, Differentiation, and Therapeutic Uses of Mesenchymal Stem Cells 2.0)

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