Mesenchymal stem cells preserve their stem cell traits after exposure to antimetabolite chemotherapy

Perez, Ramon Lopez; Münz, Franziska; Vidoni, Denise; Rühle, Alexander; Trinh, Thuy; Sisombath, Sonevisay; Zou, Bingwen; Wuchter, Patrick; Debus, Jürgen; Grosu, Anca‐Ligia; Saffrich, Rainer; Huber, Peter E.; Nicolay, Nils H.

doi:10.1016/j.scr.2019.101536

Cited by 20 publications

(9 citation statements)

References 59 publications

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“…Similar results have been reported in dental follicle-derived MSC, where the proliferation and clone formation capacity were impaired by HU accompanied by reduced MSC differentiation toward adipogenic, chondrogenic, and osteogenic lineages [54]. Conversely, treatment with other antimetabolite drugs-namely, 5-FU and gemcitabine-retain BMMSC multi-lineage differentiation potential, although no senescence analysis was performed in this study [55]. These data suggest that chemotherapy does not modify MSC differentiation markers, thus MSC may preserve their stem identity.…”

Section: Discussionsupporting

confidence: 87%

Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro

Kapor

Vukotić

Subotički

et al. 2021

JPM

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Hydroxyurea (HU) is an antineoplastic agent that functions as an antimetabolite compound by inhibiting the ribonucleotide reductase. HU acts mainly as a cytostatic drug that through DNA replication stress may trigger a premature senescence-like cell phenotype, though its influence on bone marrow-derived mesenchymal stem/stromal cell (BMMSC) functions has not elucidated yet. Our results indicate that HU inhibits the growth of human BMMSC alongside senescence-like changes in both morphology and replicative potential, provokes cell cycle arrest at the S phase without affecting cellular viability and induces the expression of senescence-associated β-galactosidase and p16INK4. Moreover, HU-induced senescent BMMSC, although they did not change MSC markers expression, exhibited reduced capacity osteogenic and adipogenic differentiation. Conversely, HU treatment increased immunoregulatory functions of BMMSC compared with untreated cells and determined by T-cell proliferation. Interestingly, HU did not influence the capacity of BMMSC to induce monocytic myeloid-derived suppressor cells. Thus, these results suggest that HU improves the BMMSC functions on the T-cell inhibition and preserves their interaction with myeloid cell compartment. Mechanistically, BMMSC under HU treatment displayed a downregulation of mTOR and p38 MAPK signaling that may explain the reduced cell differentiation and increased immunomodulation activities. Together, the results obtained in this investigation suggest that HU by inducing senescence-like phenotype of BMMSC influences their cellular differentiation and immunoregulatory functions.

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Section: Discussionsupporting

confidence: 87%

Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro

Kapor

Vukotić

Subotički

et al. 2021

JPM

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“…Along with the possibilities of culturing and upscaling MSCORS, their cell motility, metabolic activity, and immunomodulatory properties are particularly interesting both from fundamental and applicative aspects of MSC biology. We aimed at looking into these features, beginning with mitochondrial activity, usually correlated to cell proliferation and migratory propensity, as a common landmark for cell responsiveness to stimulation towards paracrine-mediated anti-inflammatory effects, a basis for chemotaxis, and ultimately regenerative potential [38,39].…”

Section: Introductionmentioning

confidence: 99%

Autologous, Non-Invasively Available Mesenchymal Stem Cells from the Outer Root Sheath of Hair Follicle Are Obtainable by Migration from Plucked Hair Follicles and Expandable in Scalable Amounts

Masieri

Schneider

et al. 2020

Cells

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Background: Regenerative therapies based on autologous mesenchymal stem cells (MSC) as well as stem cells in general are still facing an unmet need for non-invasive sampling, availability, and scalability. The only known adult source of autologous MSCs permanently available with no pain, discomfort, or infection risk is the outer root sheath of the hair follicle (ORS). Methods: This study presents a non-invasively-based method for isolating and expanding MSCs from the ORS (MSCORS) by means of cell migration and expansion in air–liquid culture. Results: The method yielded 5 million cells of pure MSCORS cultured in 35 days, thereby superseding prior art methods of culturing MSCs from hair follicles. MSCORS features corresponded to the International Society for Cell Therapy characterization panel for MSCs: adherence to plastic, proliferation, colony forming, expression of MSC-markers, and adipo-, osteo-, and chondro-differentiation capacity. Additionally, MSCORS displayed facilitated random-oriented migration and high proliferation, pronounced marker expression, extended endothelial and smooth muscle differentiation capacity, as well as a paracrine immunomodulatory effect on monocytes. MSCORS matched or even exceeded control adipose-derived MSCs in most of the assessed qualities. Conclusions: MSCORS qualify for a variety of autologous regenerative treatments of chronic disorders and prophylactic cryopreservation for purposes of acute treatments in personalized medicine.

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“…In our work, we evaluated the effects of a long-term treatment carried out after nine and eighteen days, respectively. The duration of the morphine exposition was chosen with the aim of overcoming the intrinsic ability of hMSCs to maintain their functional integrity 20 . Although we did not find an evident relation between long-term morphine exposition and apoptosis, we observed a marked cell viability decrease as well as a cytostatic effect for the highest concentrations tested.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the structural and functional characteristics of human mesenchymal stem cells associated with a prolonged exposure of morphine

Carano

Teti

Ruggeri

et al. 2021

Sci Rep

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The discovery of the expression of opioid receptors in the skin and their role in orchestrating the process of tissue repair gave rise to questions regarding the potential effects of clinical morphine treatment in wound healing. Although short term treatment was reported to improve tissue regeneration, in vivo chronic administration was associated to an impairment of the physiological healing process and systemic fibrosis. Human mesenchymal stem cells (hMSCs) play a fundamental role in tissue regeneration. In this regard, acute morphine exposition was recently reported to impact negatively on the functional characteristics of hMSCs, but little is currently known about its long-term effects. To determine how a prolonged treatment could impair their functional characteristics, we exposed hMSCs to increasing morphine concentrations respectively for nine and eighteen days, evaluating in particular the fibrogenic potential exerted by the long-term exposition. Our results showed a time dependent cell viability decline, and conditions compatible with a cellular senescent state. Ultrastructural and protein expression analysis were indicative of increased autophagy, suggesting a relation to a detoxification activity. In addition, the enhanced transcription observed for the genes involved in the synthesis and regulation of type I collagen suggested the possibility that a prolonged morphine treatment might exert its fibrotic potential risk, even involving the hMSCs.

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Mesenchymal stem cells preserve their stem cell traits after exposure to antimetabolite chemotherapy

Cited by 20 publications

References 59 publications

Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro

Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro

Autologous, Non-Invasively Available Mesenchymal Stem Cells from the Outer Root Sheath of Hair Follicle Are Obtainable by Migration from Plucked Hair Follicles and Expandable in Scalable Amounts

Assessment of the structural and functional characteristics of human mesenchymal stem cells associated with a prolonged exposure of morphine

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