Tsc1 Regulates the Proliferation Capacity of Bone-Marrow Derived Mesenchymal Stem Cells.

Maria V Guijarro,Akbar Nawab,Glyn D Palmer,Marta Cañamero,Laura S Danielson,Carolina Abrahan,Eva Hernando

doi:10.3390/cells9092072

Maria V Guijarro, Akbar Nawab + Show 5 more

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https://doi.org/10.3390/cells9092072

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Journal: Cells	Publication Date: Sep 10, 2020
Citations: 7	License type: CC BY 4.0

Affiliation: University of Florida

Abstract

TSC1 is a tumor suppressor that inhibits cell growth via negative regulation of the mammalian target of rapamycin complex (mTORC1). TSC1 mutations are associated with Tuberous Sclerosis Complex (TSC), characterized by multiple benign tumors of mesenchymal and epithelial origin. TSC1 modulates self-renewal and differentiation in hematopoietic stem cells; however, its effects on mesenchymal stem cells (MSCs) are unknown. We investigated the impact of Tsc1 inactivation in murine bone marrow (BM)-MSCs, using tissue-specific, transgelin (Tagln)-mediated cre-recombination, targeting both BM-MSCs and smooth muscle cells. Tsc1 mutants were viable, but homozygous inactivation led to a dwarfed appearance with TSC-like pathologies in multiple organs and reduced survival. In young (28 day old) mice, Tsc1 deficiency-induced significant cell expansion of non-hematopoietic BM in vivo, and MSC colony-forming potential in vitro, that was normalized upon treatment with the mTOR inhibitor, everolimus. The hyperproliferative BM-MSC phenotype was lost in aged (1.5 yr) mice, and Tsc1 inactivation was also accompanied by elevated ROS and increased senescence. ShRNA-mediated knockdown of Tsc1 in BM-MSCs replicated the hyperproliferative BM-MSC phenotype and led to impaired adipogenic and myogenic differentiation. Our data show that Tsc1 is a negative regulator of BM-MSC proliferation and support a pivotal role for the Tsc1-mTOR axis in the maintenance of the mesenchymal progenitor pool.

Highlights

Germline mutation of either TSC1 or TSC2 causes tuberous sclerosis (TSC), a multisystemic, autosomal dominant disorder with an estimated prevalence of 1 in 6000 newborns
To investigate the in vivo effects of Tsc1 inactivation, we used a Tagln-driven conditional knockout approach to enable tissue-specific targeting of smooth muscle and mesenchymal progenitors and overcome early embryonic lethality associated with global Tsc1 deletion
SA β-gal staining of Tsc1∆/∆ kidneys identified senescent cells lining cystic lesions that co-localized with areas of hyperproliferation (Figure 4E, lower panels), and were absent in Tsc1+/+ controls (Figure 4E, upper panels). These findings indicate that the proliferative phenotype associated with Tsc1 inactivation is accompanied by an onset of cellular senescence in both bone marrow (BM)-mesenchymal stem cells (MSCs) and Smooth Muscle (SM) compartments consistent with premature cell aging

Summary

Introduction

Germline mutation of either TSC1 (encoding hamartin) or TSC2 (encoding tuberin) causes tuberous sclerosis (TSC), a multisystemic, autosomal dominant disorder with an estimated prevalence of 1 in 6000 newborns. TSC is characterized by benign, focal malformations called hamartomas, which comprise nonmalignant cells exhibiting abnormal cell proliferation and differentiation [1,2]. TSC often causes disabling neurological disorders, including epilepsy, mental retardation, and autism. Renal angiomyolipomas [3], benign tumors composed of abnormal vessels, immature smooth muscle cells, and fat cells; (2) lymphangioleiomyomatosis, widespread pulmonary proliferation of abnormal. Loss of heterozygosity at the TSC1 or TSC2 locus and hyperphosphorylation of ribosomal protein S6 has been documented in each of the three cellular components of angiomyolipomas [6], suggesting that they may arise from a common progenitor and that the TSC1–TSC2 complex regulates the differentiation of cells that are derived from the mesenchyme.

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