Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard

Rothmiller, Simone; Jäger, Niklas; Meier, Nicole; Meyer, Thimo; Neu, Adrian; Steinritz, Dirk; Thiermann, Horst; Scherer, M. A.; Rummel, Christoph; Mangerich, Aswin; Bürkle, Alexander; Schmidt, Annette

doi:10.1007/s00204-020-02946-5

Cited by 8 publications

(8 citation statements)

References 66 publications

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“…Notably, senescent hMSCs were found to be resistant towards other senolytic compounds. Indeed, by analyzing the existing evidence we found that various compounds with the stated senolytic activity, including navitoclax, nicotinamide riboside, danazol geldanamycin, ganetespib, fisetin, BCL-XL inhibitors, quercetin, etomoxir, antimycin A, FOXO4-DRI, 17-DMAG turned to be ineffective for the targeted removal of senescent human preadipocytes (fibroblast like precursor cells derived from human adipose tissue) and hMSCs from bone marrow [ 17 – 19 , 36 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

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Apoptosis resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides

Deryabin

Shatrova

Borodkina

2021

Cell. Mol. Life Sci.

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Targeted elimination of senescent cells, senolysis, is one of the core trends in the anti-aging therapy. Cardiac glycosides were recently proved to be a broad-spectrum senolytics. Here we tested senolytic properties of cardiac glycosides towards human mesenchymal stem cells (hMSCs). Cardiac glycosides had no senolytic ability towards senescent hMSCs of various origins. Using biological and bioinformatic approaches we compared senescence development in ‘cardiac glycosides-sensitive’ A549 and ‘-insensitive’ hMSCs. The absence of senolysis was found to be mediated by the effective potassium import and increased apoptosis resistance in senescent hMSCs. Weakening “antiapoptotic defense” predisposes hMSCs to senolysis. We revealed that apoptosis resistance, previously recognized as a common characteristic of senescence, in fact, is not a general feature of senescent cells. Moreover, only apoptosis-prone senescent cells are sensitive to cardiac glycosides-induced senolysis. Thus, we can speculate that the effectiveness of senolysis might depend on whether senescent cells indeed become apoptosis-resistant as compared to their proliferating counterparts. Graphic abstract

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Section: Discussionmentioning

confidence: 99%

“…In line with this suggestion, a number of reviews highlighting possible advantageous outcomes of senescent MSCs removal has been published over the past year [29,31,34,35]. Nevertheless, there are only few experimental data regarding this issue [36][37][38][39][40].…”

Section: Introductionmentioning

confidence: 99%

Apoptosis resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides

Deryabin

Shatrova

Borodkina

2021

Cell. Mol. Life Sci.

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“…In this study, the effects of single-dose SM exposure on HDF were investigated which provides new insight into the pathomechanism of SM-associated wound healing disorder. Previously published research demonstrated that senescent fibroblasts play an important role in chronic wounds and that single-dose SM exposure induces senescence in MSC which may also contribute to chronic wound healing disorders (desJardins-Park et al 2018 ; Rothmiller et al 2021 ). The results of this study hereby confirm for the first time that senescence can also be induced in HDF by SM exposure in a time- and concentration-dependent manner which was detected using different markers of senescence.…”

Section: Discussionmentioning

confidence: 99%

“…In consequence, there are no specific treatment options, neither antidotes nor a prophylaxis available (Etemad et al 2019 ). Recently, Rothmiller et al ( 2021 ) found that SM induces chronic senescence in human mesenchymal stem cells (MSC) which is considered to contribute to the wound healing disorder. As HDF also play a crucial role in wound healing, they might be affected during SM exposure.…”

Section: Introductionmentioning

confidence: 99%

Sulfur mustard single-dose exposure triggers senescence in primary human dermal fibroblasts

Horn¹,

Schäfers²,

Thiermann³

et al. 2022

Arch Toxicol

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Chronic wounds, skin blisters, and ulcers are the result of skin exposure to the alkylating agent sulfur mustard (SM). One potential pathomechanism is senescence, which causes permanent growth arrest with a pro-inflammatory environment and may be associated with a chronic wound healing disorder. SM is known to induce chronic senescence in human mesenchymal stem cells which are subsequently unable to fulfill their regenerative function in the wound healing process. As dermal fibroblasts are crucial for cutaneous wound healing by being responsible for granulation tissue formation and synthesis of the extracellular matrix, SM exposure might also impair their function in a similar way. This study, therefore, investigated the SM sensitivity of primary human dermal fibroblasts (HDF) by determining the dose–response curve. Non-lethal concentrations LC1 (3 µM) to LC25 (65 µM) were used to examine the induction of senescence. HDF were exposed once to 3 µM, 13 µM, 24 µM, 40 µM or 65 μM SM, and were then cultured for 31 days. Changes in morphology as well as at the genetic and protein level were investigated. For the first time, HDF were shown to undergo senescence in a time- and concentration-dependent manner after SM exposure. They developed a characteristic senescence phenotype and expressed various senescence markers. Proinflammatory cytokines and chemokines were significantly altered in SM-exposed HDF as part of a senescence-associated secretory phenotype. The senescent fibroblasts can thus be considered a contributor to the SM-induced chronic wound healing disorder and might serve as a new therapeutic target in the future.

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“…The major and important drugs involve in alkylating agents are cyclophosphamide, mechlorethanamine, platinum analogues, procarbazine and other alkylating agents like busulfan, carmustine and lomustine. These drugs are used in breast cancer, ovarian cancer, non-hodgkin lymphoma, chronic lymphocytic leukemia and neuroblastoma (Rothmiller et al, 2021). Its acute and chronic toxicity include nausea, vomiting myelosuppression and hemorrhagic cystitis.…”

Section: Alkylating Agentsmentioning

confidence: 99%

Biochemistry of Drugs Action and their Resistance Mechanism: A Brief Discussion

Bukhari

Tariq

Rehman

et al. 2021

FCS

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Pharmaceutical drug is a chemical substance which is used to maintain growth, cure, treat, prevent and diagnose a disease. Up to the middle of the nineteenth century, man had access to a wide range of natural remedies to ease his suffering. As part of pharmacodynamics, we consider both drug activity and drug effect, which refers to the first effects of therapeutic receptor contact and the effects that follow. Infections are a leading cause of mortality in the underdeveloped nations. This is primarily owing to the advent of emerging infectious agents, more particularly the emergence of antibiotic resistance. Drug resistance or Antimicrobial resistance (AMR), progresses when microbes, including parasites i.e viruses, bacteria and fungi no longer effective against a drug that formerly treated them effectually. Clinicians will benefit from a better grasp of the processes of antibiotic resistance when it comes to prescribing antibiotic. As a result of this review, researchers are encouraged to apply gene manipulation, increased usage of stem cells (adult and embryonic), and improve bioavailability of nutrients utilizing nanotechnology in order to overcome the negative effects of pharmaceutical medications.

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Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard

Cited by 8 publications

References 66 publications

Apoptosis resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides

Apoptosis resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides

Sulfur mustard single-dose exposure triggers senescence in primary human dermal fibroblasts

Biochemistry of Drugs Action and their Resistance Mechanism: A Brief Discussion

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