4.8 Article

Human Pluripotent Stem Cell-Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis

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CANCER RESEARCH
卷 77, 期 20, 页码 5491-5502

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-0925

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  1. McEwen Centre for Regenerative Medicine
  2. Green Eggs and LAM
  3. United States Department of Defense via the Tuberous Sclerosis Complex Research Program of the Congressionally Directed Medical Research Program [W81XWH-14-1- 0434]
  4. National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH [R01AR062080]
  5. Canadian Institutes of Health Research [FDN 143278]
  6. Intramural Research Program, NIH, National Heart, Lung, and Blood Institute
  7. LAM Foundation
  8. LAM Canada
  9. Lucy J. Engles TSC/LAM Research Program
  10. Ontario Institute for Regenerative Medicine
  11. CIHR Banting Postdoctoral Fellowships
  12. Tier 1 Canada Research Chair in Integrative Stem Cell Biology

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Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here, we generated a robust human cell model of LAM by reprogramming TSC2 mutation-bearing fibroblasts from a patient with both tuberous sclerosis complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSC), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2(-/-) mutation and recapitulated the molecular and functional characteristics of pulmo-nary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploin-sufficiency at the TSC2 locus contributes to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM that can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM. (C) 2017 AACR.

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