Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product—progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.

Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction

“…CS patients frequently exhibit musculoskeletal abnormalities, such as kyphosis, contracture and osteoporosis (Hishiya and Watanabe, 2004;Karikkineth et al, 2017). MSCs are multipotent mesodermal cells that can differentiate into a variety of mesodermal cell types, including osteoblasts, chondrocytes, and adipocytes, which serve as a good cell model for investigating the accelerated degeneration of mesodermal tissues caused by genetic mutations (Liu et al, 2014;Zhang et al, 2015Zhang et al, , 2019Kubben et al, 2016;Li et al, 2016;Pan et al, 2016;Geng et al, 2018;Wang et al, 2018b;Wu et al, 2018;Yan et al, 2019). Therefore, we first differentiated CS-iPSCs and GC-iPSCs into MSCs to investigate whether ERCC6 mutations could result in accelerated attrition of the MSC pool.…”

Super-resolution fluorescence-assisted diffraction computational tomography reveals the three-dimensional landscape of the cellular organelle interactome

“…Therefore, DBs may facilitate the exchange of material and information among different organelles, some of which are possibly ultimately transported to the plasma membrane. Interestingly, different types of ageing stem cells, which are known to be affected by alterations in the nuclear membrane 36,37 , exhibited a phenotype-associated increase in the number of DBs in hMSCs. These data suggest that nuclear information can be transmitted to DBs either directly or indirectly via DE-nuclear membrane contacts.…”

“…S14). Interestingly, in different types of ageing human mesenchymal stem cells (hMSCs) 36,37 , DBs were associated with a severe ageing phenotype ( Supplementary Fig. S15, Supplementary Videos 28-31).…”

Diabetes mellitus coexisted with progeria: a case report of atypical Werner syndrome with novel LMNA mutations and literature review

“…Administration of a specific adipokine, such as leptin, and transplantation of subcutaneous fat may induce sustained improvements in hyperglycemia, dyslipidemia, and hepatic steatosis caused by lipodystrophies [24]. It is alternative to use surgery for refractory ulcers of WS [25] and cataract [16], anti-aging treatment such as vitamin C [26], rapamycin [17] or combined with farnesyltransferase inhibitor [27], pluripotent stem cell [28,29]. Annual screening for tumor and cataracts is important for early detection of the complications, especially in patients with CWS.…”

“…Similarly, attention must be paid/ given to arteriosclerosis-related diseases in WS patients, particularly in AWS patients [6,17]. In the future, multiomics technologies, including genomics, epigenomics, and transcriptomics as well as proteomics and metabonomics are expected to provide new approaches for the prevention and treatment of aging-related disorders [29].…”