Mesenchymal stem cells derived from patients with premature aging syndromes display hallmarks of physiological aging

Trani, Jean Philippe; Chevalier, Raphaël; Caron, Leslie; Yazidi, Claire El; Broucqsault, Natacha; Toury, Léa; Thomas, Morgane; Annab, Karima; Binétruy, Bernard; Sandre-Giovannoli, Annachiara De; Lévy, Nicolas; Magdinier, Frédérique; Robin, Jérôme D.

doi:10.26508/lsa.202201501

Cited by 3 publications

(2 citation statements)

References 75 publications

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“…Taken together, the analysis above of our panel of patient cells provides a firm foundation for further studies. While partial characterization of some nuclear phenotypes or SDS-PAGE analysis for patient cells with two of these mutations ( LMNA -M540T and -C588R) has been previously published [ 51 , 57 , 58 ], here we present for the first time a systematic analysis of these, as well as the LMNA mutations E138K and D325N and the ZMPSTE24 mutations P248L and L425P.…”

Section: Resultsmentioning

confidence: 99%

The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B

Odinammadu,

Shilagardi,

Tuminelli

et al. 2023

Nucleus

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Several related progeroid disorders are caused by defective post-translational processing of prelamin A, the precursor of the nuclear scaffold protein lamin A, encoded by LMNA . Prelamin A undergoes farnesylation and additional modifications at its C-terminus. Subsequently, the farnesylated C-terminal segment is cleaved off by the zinc metalloprotease ZMPSTE24. The premature aging disorder Hutchinson Gilford progeria syndrome (HGPS) and a related progeroid disease, mandibuloacral dysplasia (MAD-B), are caused by mutations in LMNA and ZMPSTE24 , respectively, that result in failure to process the lamin A precursor and accumulate permanently farnesylated forms of prelamin A. The farnesyl transferase inhibitor (FTI) lonafarnib is known to correct the aberrant nuclear morphology of HGPS patient cells and improves lifespan in children with HGPS. Importantly, and in contrast to a previous report, we show here that FTI treatment also improves the aberrant nuclear phenotypes in MAD-B patient cells with mutations in ZMPSTE24 (P248L or L425P). As expected, lonafarnib does not correct nuclear defects for cells with lamin A processing-proficient mutations. We also examine prelamin A processing in fibroblasts from two individuals with a prevalent laminopathy mutation LMNA -R644C. Despite the proximity of residue R644 to the prelamin A cleavage site, neither R644C patient cell line shows a prelamin A processing defect, and both have normal nuclear morphology. This work clarifies the prelamin A processing status and role of FTIs in a variety of laminopathy patient cells and supports the FDA-approved indication for the FTI Zokinvy for patients with processing-deficient progeroid laminopathies, but not for patients with processing-proficient laminopathies.

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Section: Resultsmentioning

confidence: 99%

The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B

Odinammadu,

Shilagardi,

Tuminelli

et al. 2023

Nucleus

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“…The differentially expressed genes (DEGs) in MSCs derived from premature aging syndromes (PAS) compared to MSCs derived from individuals without these syndromes primarily revolve around DNA double-strand damage, telomere damage, and DNA methylation. These genetic changes are associated with the impaired differentiation of MSCs( Trani et al, 2022 ). In response to these alterations in MSCs, the application of MSC-based cell therapies combined with genetic engineering can provide a safe and effective method for individuals to produce factors that are needed by cells in recipient organs with enzymatic or other defects ( Meyerrose et al, 2010 ) ( Tables 1 and 2 ).…”

Section: Effects Of Different Cellular Microenvironments On Mscs' Sen...mentioning

confidence: 99%

Cellular microenvironment: a key for tuning mesenchymal stem cell senescence

Sun,

Lv,

Guo

et al. 2023

Front. Cell Dev. Biol.

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Mesenchymal stem cells (MSCs) possess the ability to self-renew and differentiate into multiple cell types, making them highly suitable for use as seed cells in tissue engineering. These can be derived from various sources and have been found to play crucial roles in several physiological processes, such as tissue repair, immune regulation, and intercellular communication. However, the limited capacity for cell proliferation and the secretion of senescence-associated secreted phenotypes (SASPs) pose challenges for the clinical application of MSCs. In this review, we provide a comprehensive summary of the senescence characteristics of MSCs and examine the different features of cellular microenvironments studied thus far. Additionally, we discuss the mechanisms by which cellular microenvironments regulate the senescence process of MSCs, offering insights into preserving their functionality and enhancing their effectiveness.

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Neural synchrony in cortical networks: mechanisms and implications for neural information processing and coding

Gansel¹

2022

Front. Integr. Neurosci.

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Synchronization of neuronal discharges on the millisecond scale has long been recognized as a prevalent and functionally important attribute of neural activity. In this article, I review classical concepts and corresponding evidence of the mechanisms that govern the synchronization of distributed discharges in cortical networks and relate those mechanisms to their possible roles in coding and cognitive functions. To accommodate the need for a selective, directed synchronization of cells, I propose that synchronous firing of distributed neurons is a natural consequence of spike-timing-dependent plasticity (STDP) that associates cells repetitively receiving temporally coherent input: the “synchrony through synaptic plasticity” hypothesis. Neurons that are excited by a repeated sequence of synaptic inputs may learn to selectively respond to the onset of this sequence through synaptic plasticity. Multiple neurons receiving coherent input could thus actively synchronize their firing by learning to selectively respond at corresponding temporal positions. The hypothesis makes several predictions: first, the position of the cells in the network, as well as the source of their input signals, would be irrelevant as long as their input signals arrive simultaneously; second, repeating discharge patterns should get compressed until all or some part of the signals are synchronized; and third, this compression should be accompanied by a sparsening of signals. In this way, selective groups of cells could emerge that would respond to some recurring event with synchronous firing. Such a learned response pattern could further be modulated by synchronous network oscillations that provide a dynamic, flexible context for the synaptic integration of distributed signals. I conclude by suggesting experimental approaches to further test this new hypothesis.

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Mesenchymal stem cells derived from patients with premature aging syndromes display hallmarks of physiological aging

Cited by 3 publications

References 75 publications

The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B

The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B

Cellular microenvironment: a key for tuning mesenchymal stem cell senescence

Neural synchrony in cortical networks: mechanisms and implications for neural information processing and coding

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