Biological functions of mesenchymal stem cells and clinical implications

Naji, Abderrahim; Eitoku, Masamitsu; Favier, Benoît; Deschaseaux, Frédéric; Rouas‐Freiss, Nathalie; Suganuma, Narufumi

doi:10.1007/s00018-019-03125-1

Cited by 414 publications

(326 citation statements)

References 365 publications

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“…Cell morphology was studied on whole populations of primary hBM-MSCs obtained from each donor and at single-cell resolution (2). After culturing hBM-MSCs in standard medium for 48 hours, the cells were fixed, stained for cytoskeletal fibers, and visualized using automated fluorescence microscope (Operetta HCS) (Perkin Elmer).…”

Section: Study Workflowmentioning

confidence: 99%

“…The efficacy of hBM‐MSCs transplantation to enhance skeletal and non‐skeletal tissue regeneration, for example, following bone fracture, cartilage injury, as well as cardiovascular and immune diseases, is being examined in a large number of clinical trials. The rationale is that hBM‐MSCs can differentiate into functional bone forming osteoblastic cells (skeletal applications) or produce a large number of cytokines and growth factors (so‐called cytokine factory) that improve tissue regeneration (non‐skeletal applications) . Although MSCs‐like cells have been isolated from different tissues such as adipose tissues, placenta, and Wharton's jelly of umbilical cord, bone marrow is considered the standard source for MSCs with in vitro and in vivo bone‐forming ability and is the basis for their clinical use for enhancing bone tissue formation.…”

Section: Introductionmentioning

confidence: 99%

“…The rationale is that hBM-MSCs can differentiate into functional bone forming osteoblastic cells (skeletal applications) or produce a large number of cytokines and growth factors (so-called cytokine factory) that improve tissue regeneration (non-skeletal applications). [2][3][4] Although MSCs-like cells have been isolated from different tissues such as adipose tissues, placenta, and Wharton's jelly of umbilical cord, bone marrow is considered the standard source for MSCs with in vitro and in vivo bone-forming ability 1,5,6 and is the basis for their clinical use for enhancing bone tissue formation.…”

Section: Introductionmentioning

confidence: 99%

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Single-cell high-content imaging parameters predict functional phenotype of cultured human bone marrow stromal stem cells

Kowal

Schmal

Halekoh

et al. 2019

Stem Cells Translational Medicine

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Cultured human bone marrow stromal (mesenchymal) stem cells (hBM-MSCs) are heterogenous cell populations exhibiting variable biological properties. Quantitative high-content imaging technology allows identification of morphological markers at a single cell resolution that are determinant for cellular functions. We determined the morphological characteristics of cultured primary hBM-MSCs and examined their predictive value for hBM-MSC functionality. BM-MSCs were isolated from 56 donors and characterized for their proliferative and differentiation potential. We correlated these data with cellular and nuclear morphological features determined by Operetta; a high-content imaging system. Cell area, cell geometry, and nucleus geometry of cultured hBM-MSCs exhibited significant correlation with expression of hBM-MSC membrane markers: ALP, CD146, and CD271. Proliferation capacity correlated negatively with cell and nucleus area and positively with cytoskeleton texture features. In addition, in vitro differentiation to osteoblasts as well as in vivo heterotopic bone formation was associated with decreased ratio of nucleus width to length. Multivariable analysis applying a stability selection procedure identified nuclear geometry and texture as predictors for hBM-MSCs differentiation potential to osteoblasts or adipocytes. Our data demonstrate that by employing a limited number of cell morphological characteristics, it is possible to predict the functional phenotype of cultured hBM-MSCs and thus can be used as a screening test for "quality" of hBM-MSCs prior their use in clinical protocols. K E Y W O R D Scell and nucleus morphology, high-content imaging, human stromal/mesenchymal stem cells, osteoblastic and adipocytic differentiation, proliferation

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Section: Study Workflowmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Single-cell high-content imaging parameters predict functional phenotype of cultured human bone marrow stromal stem cells

Kowal

Schmal

Halekoh

et al. 2019

Stem Cells Translational Medicine

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“…Hence, MSCs hold important interest in cell therapy and regenerative medicine . MSCs were first identified in bone marrow (BM‐MSCs), which remains their main biological source in research and cell therapy . Alternatively, adipose‐derived stromal cells (ASCs) are MSCs accessible from adipose tissue, by simple procedures and at high cell yield …”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the differentiation of hASCs and/or the conversion of white adipocytes into beige adipocytes are of clinical interest . By affecting ASC functionality but lacking standardization, hASC culture represents a major bottleneck and deserves specific attention . For expanding hASCs, we used the endothelial cell growth medium 2 (EGM2), designed for culturing endothelial and perivascular cells, a physiological location common to hASCs .…”

Section: Introductionmentioning

confidence: 99%

Cell immaturity and white/beige adipocyte potential of primary human adipose-derived stromal cells are restrained by culture-medium TGFβ1

et al. 2020

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Human adipose-derived stem/stromal cells (hASCs) can differentiate into specialized cell types and thereby contribute to tissue regeneration. As such, hASCs have drawn increasing attention in cell therapy and regenerative medicine, not to mention the ease to isolate them from donors. Culture conditions are critical for expanding hASCs while maintaining optimal therapeutic capabilities. Here, we identified a role for transforming growth factor β1 (TGFβ1) in culture medium in influencing the fate of hASCs during in vitro cell expansion. Human ASCs obtained after expansion in standard culture medium (Standard-hASCs) and in endothelial cell growth medium 2 (EGM2-hASCs) were characterized by high-throughput transcriptional studies, gene set enrichment analysis and functional properties. EGM2-hASCs exhibited enhanced multipotency capabilities and an immature phenotype compared with Standard-hASCs. Moreover, the adipogenic potential of EGM2-hASCs was enhanced, including toward beige adipogenesis, compared with Standard-hASCs. In these conditions, TGFβ1 acts as a critical factor affecting the immaturity and multipotency of Standard-hASCs, as suggested by small mother of decapentaplegic homolog 3 (SMAD3) nuclear localization and phosphorylation in Standard-hASCs vs EGM2-hASCs. Finally, the typical priming of Standard-hASCs into osteoblast, chondroblast, and vascular smooth muscle cell (VSMC) lineages was counteracted by pharmacological inhibition of the TGFβ1 receptor, which allowed retention of SMAD3 into the cytoplasm and a decrease in expression of osteoblast and VSMC lineage markers. Overall, the TGFβ1 pathway appears critical in influencing the commitment of hASCs toward osteoblast, chondroblast, and VSMC lineages, thus reducing their adipogenic potential. These effects can be counteracted by using EGM2 culture medium or chemical inhibition of the TGFβ1 pathway.Abbreviations: ASCs, adipose-derived stem/stromal cells; BM-MSCs, bone marrow mesenchymal stem/stromal cells; BMP, bone morphogenetic protein; CFU-f, colony-forming unit fibroblast; EGM2, endothelial cell growth medium 2; FBS, fetal bovine serum; GO, Gene Ontology; GSEA, gene set enrichment analysis; hrTGFβ1, human recombinant transforming growth factor-beta 1; MEM, minimum essential media; MSCs, mesenchymal stem/stromal cells; PCA, principal component analysis; SMAD, small mother of decapentaplegic homolog; SVF, stromal vascular fraction;TGFβ1R, transforming growth beta 1 receptor; TGFβR1, transforming growth beta receptor type 1; UCP1, uncoupling protein 1; VSMCs, vascular smooth muscle cells.

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