Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome

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Hutchinson–Gilford progeria syndrome (HGPS) is a rare and fatal human premature ageing disease1,2,3,4,5, characterized by premature arteriosclerosis and degeneration of vascular smooth muscle cells (SMCs)6,7,8. HGPS is caused by a single point mutation in the lamin A (LMNA) gene, resulting in the generation of progerin, a truncated splicing mutant of lamin A. Accumulation of progerin leads to various ageing-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin9,10,11,12. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature ageing. Upon differentiation of HGPS-iPSCs, progerin and its ageing-associated phenotypic consequences are restored. Specifically, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescence phenotypes associated with vascular ageing. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs, also known as PRKDC) as a downstream target of progerin. The absence of nuclear DNAPK holoenzyme correlates with premature as well as physiological ageing. Because progerin also accumulates during physiological ageing6,12,13, our results provide an in vitro iPSC-based model to study the pathogenesis of human premature and physiological vascular ageing.

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Figure 1: Generation of iPSCs from HGPS fibroblasts.
Figure 2: HGPS-associated nuclear defects are reset in HGPS-iPSCs.
Figure 3: SMCs expressing progerin show nuclear defects and accelerated senescence.
Figure 4: Decreased expression of DNAPK holoenzyme correlates with premature cell ageing.

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Gene Expression Omnibus

Data deposits

Microarray data have been deposited in NCBI-GEO under the accession number GSE24487.


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We thank L. Comai for providing experimental material, M. Hetzer, J. Karlseder, J.-F. Deleuze, M. J. Barrero, C. Rodriguez Esteban and L. Gerace for helpful discussions, M. Marti for teratoma analysis, M. C. Llach for karyotyping, T. Berggren, M. Lutz, I. Dubova, S. Stewart, R. Dev, M. Li, L. Laricchia-Robbio, A. M. Goebl and J. Kim for technical help, and M. Schwarz for administrative help. G.-H.L. and L.K. were partially supported by a CIRM grant (TG2-01158), J.Q. was partially supported by an AFAR/Ellison Medical Foundation postdoctoral fellowship; A.D.P. was partially supported by a NIH training grant T32 CA009370. This study was supported by grants from NIH R01-DA025779 (K.Z.), and NIH P41 RR011823 (J.Y.); the G. Harold and Leila Y. Mathers Charitable Foundation, Sanofi-Aventis, Ellison Medical Foundation, MICINN and Fundacion Cellex (JCIB).

Author information

G.-H.L. and J.C.I.B. conceived the experiments; G.-H.L., B.Z.B., S.R., D.D., J.Q., S.-L.Y., A.D.P., K.S., L.K., C.W., J.T. and H.L.F. performed the experiments and analysed the data; S.B., I.S.-M., K.Z., J.Y. and J.C.I.B. analysed the data; G.-H.L., S.R., B.Z.B., A.D.P., K.Z. and J.C.I.B. wrote the manuscript.

Correspondence to Juan Carlos Izpisua Belmonte.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-18 with legends. (PDF 11678 kb)

Supplementary Table 1

This table contains the DNA methylation parameters. (DOC 30 kb)

Supplementary Table 2

This table contains the genes within 10kb of a differentially methylated region (DMR) found between BJ and HGPS fibroblasts. (XLS 356 kb)

Supplementary Table 3

This table contains the genes within 10kb of a differentially methylated region (DMR) found between BJ-iPSCs and HGPS-iPSCs. (XLS 77 kb)

Supplementary Table 4

This table contains the peptides identified by MudPIT for the indicated candidate progerin-associated partners. (DOC 58 kb)

Supplementary Table 5

This table contains the primers used in this study. (DOC 101 kb)

Supplementary Movie 1

In this movie we see the contracting area derived from BJ-iPSC colony following directed differentiation into cardiac tissue. Movies were taken at day 12 of embryoid body development. (MOV 6503 kb)

Supplementary Movie 2

In this movie we see HGPS-iPSCs develop into contractile cardiac tissue with pacemaker activity in vitro. Movies were taken at day 12 of embryoid body development. (MOV 10026 kb)

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