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Microtubule-interacting drugs induce moderate and reversible damage to human bone marrow mesenchymal stem cells.

ABSTRACT: OBJECTIVES:This study aimed to investigate molecular and cellular changes induced in human bone marrow mesenchymal stem cells (hMSCs) after treatment with microtubule-interacting agents and to estimate damage to the bone marrow microenvironment caused by chemotherapy. MATERIALS AND METHODS:Using an in vitro hMSC culture system and biochemical and morphological approaches, we studied the effect of nocodazole and taxol(R) on microtubule and nuclear envelope organization, tubulin and p53 synthesis, cell cycle progression and proliferation and death of hMSCs isolated from healthy donors. RESULTS AND CONCLUSIONS:Both nocodazole and taxol reduced hMSC proliferation and induced changes in the microtubular network and nuclear envelope morphology and organization. However, they exhibited only a moderate effect on cell death and partial arrest of hMSCs at G(2) but not at M phase of the cell cycle. Both agents induced expression of p53, exclusively localized in abnormally shaped nuclei, while taxol, but not nocodazole, increased synthesis of beta-tubulin isoforms. Cell growth rates and microtubule and nuclear envelope organization gradually normalized after transfer, in drug-free medium. Our data indicate that microtubule-interacting drugs reversibly inhibit proliferation of hMSCs; additionally, their cytotoxic action and effect on microtubule and nuclear envelope organization are moderate and reversible. We conclude that alterations in human bone marrow cells of patients under taxol chemotherapy are transient and reversible.

SUBMITTER: Polioudaki H

PROVIDER: S-EPMC6495966 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Microtubule-interacting drugs induce moderate and reversible damage to human bone marrow mesenchymal stem cells.

Polioudaki H H Kastrinaki M-C MC Papadaki H A HA Theodoropoulos P A PA

Cell proliferation 20090522 4

<h4>Objectives</h4>This study aimed to investigate molecular and cellular changes induced in human bone marrow mesenchymal stem cells (hMSCs) after treatment with microtubule-interacting agents and to estimate damage to the bone marrow microenvironment caused by chemotherapy.<h4>Materials and methods</h4>Using an in vitro hMSC culture system and biochemical and morphological approaches, we studied the effect of nocodazole and taxol(R) on microtubule and nuclear envelope organization, tubulin and ...[more]

PMID: 19486015

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Project description:Environmental obesogens are a newly recognized category of endocrine disrupting chemicals that have been implicated in contributing to the rising rates of obesity in the United States. While obesity is typically regarded as an increase in visceral fat, adipocyte accumulation in the bone has been linked to increased fracture risk, lower bone density, and osteoporosis. Exposure to environmental toxicants that activate peroxisome proliferator activated receptor ? (PPAR?), a critical regulator of the balance of differentiation between adipogenesis and osteogenesis, may contribute to the increasing prevalence of osteoporosis. However, induction of adipogenesis and suppression of osteogenesis are separable activities of PPAR?, and ligands may selectively alter these activities. It currently is unknown whether suppression of osteogenesis is a common toxic endpoint of environmental PPAR? ligands. Using a primary mouse bone marrow culture model, we tested the hypothesis that environmental toxicants acting as PPAR? agonists divert the differentiation pathway of bone marrow-derived multipotent mesenchymal stromal cells towards adipogenesis and away from osteogenesis. The toxicants tested included the organotins tributyltin and triphenyltin, a ubiquitous phthalate metabolite (mono-(2-ethylhexyl) phthalate, MEHP), and two brominated flame retardants (tetrabromobisphenol-a, TBBPA, and mono-(2-ethylhexyl) tetrabromophthalate, METBP). All of the compounds activated PPAR?1 and 2. All compounds increased adipogenesis (lipid accumulation, Fabp4 expression) and suppressed osteogenesis (alkaline phosphatase activity, Osx expression) in mouse primary bone marrow cultures, but with different potencies and efficacies. Despite structural dissimilarities, there was a strong negative correlation between efficacies to induce adipogenesis and suppress osteogenesis, with the organotins being distinct in their exceptional ability to suppress osteogenesis. As human exposure to a mixture of toxicants is likely, albeit at low doses, the fact that multiple toxicants are capable of suppressing bone formation supports the hypothesis that environmental PPAR? ligands represent an emerging threat to human bone health.

Dataset Information

Microtubule-interacting drugs induce moderate and reversible damage to human bone marrow mesenchymal stem cells.

Publications

Microtubule-interacting drugs induce moderate and reversible damage to human bone marrow mesenchymal stem cells.

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