Functional heterogeneity of mesenchymal stem cells from natural niches to culture conditions: implications for further clinical uses

Costa, Luis A.; Eiró, Noemí; Fraile, María; González, Luis O.; Saá, Jorge; Garcia-Portabella, Pablo; Vega, Belén; Schneider, J.

doi:10.1007/s00018-020-03600-0

Cited by 190 publications

(172 citation statements)

References 242 publications

(321 reference statements)

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“…First, the functional heterogeneity of stem cells is a substantial obstacle to their clinical transformation [ 211 ]. Therefore, before using stem cells, it is necessary to screen out specific subgroups to more accurately explore the molecular mechanism of cartilage regeneration.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Research Progress on Stem Cell Therapies for Articular Cartilage Regeneration

Jiang

Tian

et al. 2021

Stem Cells International

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Injury of articular cartilage can cause osteoarthritis and seriously affect the physical and mental health of patients. Unfortunately, current surgical treatment techniques that are commonly used in the clinic cannot regenerate articular cartilage. Regenerative medicine involving stem cells has entered a new stage and is considered the most promising way to regenerate articular cartilage. In terms of theories on the mechanism, it was thought that stem cell-mediated articular cartilage regeneration was achieved through the directional differentiation of stem cells into chondrocytes. However, recent evidence has shown that the stem cell secretome plays an important role in biological processes such as the immune response, inflammation regulation, and drug delivery. At the same time, the stem cell secretome can effectively mediate the process of tissue regeneration. This new theory has attributed the therapeutic effect of stem cells to their paracrine effects. The application of stem cells is not limited to exogenous stem cell transplantation. Endogenous stem cell homing and in situ regeneration strategies have received extensive attention. The application of stem cell derivatives, such as conditioned media, extracellular vesicles, and extracellular matrix, is an extension of stem cell paracrine theory. On the other hand, stem cell pretreatment strategies have also shown promising therapeutic effects. This article will systematically review the latest developments in these areas, summarize challenges in articular cartilage regeneration strategies involving stem cells, and describe prospects for future development.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Research Progress on Stem Cell Therapies for Articular Cartilage Regeneration

Jiang

Tian

et al. 2021

Stem Cells International

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“…Minimal criteria to define hMSC in vitro comprise their plastic adherence, the expression of specific mesenchymal markers and the absence of hematopoietic markers, as well as their capacity to differentiate toward the osteogenic, adipogenic, and chondrogenic lineage [ 1 , 2 ]. The cultivation duration of primary hMSC is limited, because cells in culture undergo the process of replicative senescence [ 3 ]. This characteristic, as well as their heterogeneity, makes it difficult to use them for the establishment of standardized procedures.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Glycoengineering in hMSC-TERT as a Model for Skeletal Precursors by Using Modified Azide/Alkyne Monosaccharides

Altmann

Mut

Wolf

et al. 2021

IJMS

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Metabolic glycoengineering enables a directed modification of cell surfaces by introducing target molecules to surface proteins displaying new features. Biochemical pathways involving glycans differ in dependence on the cell type; therefore, this technique should be tailored for the best results. We characterized metabolic glycoengineering in telomerase-immortalized human mesenchymal stromal cells (hMSC‑TERT) as a model for primary hMSC, to investigate its applicability in TERT-modified cell lines. The metabolic incorporation of N‑azidoacetylmannosamine (Ac4ManNAz) and N‑alkyneacetylmannosamine (Ac4ManNAl) into the glycocalyx as a first step in the glycoengineering process revealed no adverse effects on cell viability or gene expression, and the in vitro multipotency (osteogenic and adipogenic differentiation potential) was maintained under these adapted culture conditions. In the second step, glycoengineered cells were modified with fluorescent dyes using Cu-mediated click chemistry. In these analyses, the two mannose derivatives showed superior incorporation efficiencies compared to glucose and galactose isomers. In time-dependent experiments, the incorporation of Ac4ManNAz was detectable for up to six days while Ac4ManNAl-derived metabolites were absent after two days. Taken together, these findings demonstrate the successful metabolic glycoengineering of immortalized hMSC resulting in transient cell surface modifications, and thus present a useful model to address different scientific questions regarding glycosylation processes in skeletal precursors.

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“…More senescent cells were found in MSCs isolated from elderly people even at the initial cell passage, and these MSCs had decreased proliferation and differentiation potential compared those from younger donors [11,12]. Except for age, obesity and health status may also affect MSCs action [13]. MSCs derived from donors of obesity [14] and/ or donors with systemic diseases [15] are dysfunctional.…”

Section: Discussionmentioning

confidence: 99%

Cell Heterogeneity, Rather Than Cell Solvents Affects the Behavior of Mesenchymal Stem Cells in Vitro and Vivo

Wang

Tao

et al. 2020

Preprint

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Background: Mesenchymal stem cells (MSCs) have been approved to treat various diseases, but they have to be expanded in vitro to gain sufficient cell doses. During the process of expansion, some obstacles remain to be addressed before MSCs translation to clinic. The purpose of this study was to investigate the effects of cell solvents and cell heterogeneity on the behavior of MSCs in vitro and vivo.Methods: Human umbilical cord MSCs (UC-MSCs) were dissolved in three different solvents: phosphate buffer solution (PBS), normal saline (NS) and dulbecco's modified eagle medium (DMEM). Their ultrastructure, viability and safety were explored and compared. MSCs from other two separate donors were grouped based on their mean diameters. The ultrastructure, proliferative and hepatic differentiation potential, senescent cell ratio and safety of the two UC-MSC aggregates were investigated and compared. The reason for mice death after UC-MSCs injection was further investigated.Results: The apoptosis rates, ultrastructure analysis and survival rates of mice among UC-MSCs in DMEM, NS and PBS were similar, and no significant differences were observed. The diameters of UC-MSCs of different sizes were measured. Cells with diameter of 15.58±3.813 μm were renamed as larger UC-MSC aggregates and cells with diameter of 19.14±4.885 μm were smaller aggregates. The mean diameter of larger MSC aggregates was significantly longer than that of smaller aggregates (p<0.01). Smaller MSCs had more potent proliferation potential and higher nucleus/ cytoplasm ratio than large ones. The number of cells positive for senescence-associated β-galactosidase staining was higher in larger UC-MSC aggregates. The survival rates of mice receiving 1×106 or 2×106 smaller MSCs were 100%, both higher than that receiving larger UC-MSCs sharing same amount. Meanwhile, the reason for mice death was explored and it revealed that larger UC-MSC aggregates were accumulated and evident in the pulmonary capillary lumen in dead mice.Conclusion: Solvents showed no significant effects on cell behavior, whereas, heterogeneity is quite prevalent in MSCs populations and may limit cell application, but it is easily overlooked. Hence it is necessary to establish a more precise standardization for culture-expanded MSCs and to improve MSCs manufacturing strategies.

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Functional heterogeneity of mesenchymal stem cells from natural niches to culture conditions: implications for further clinical uses

Cited by 190 publications

References 242 publications

Research Progress on Stem Cell Therapies for Articular Cartilage Regeneration

Research Progress on Stem Cell Therapies for Articular Cartilage Regeneration

Metabolic Glycoengineering in hMSC-TERT as a Model for Skeletal Precursors by Using Modified Azide/Alkyne Monosaccharides

Cell Heterogeneity, Rather Than Cell Solvents Affects the Behavior of Mesenchymal Stem Cells in Vitro and Vivo

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