Abstract

Our goal is to test mesenchymal stem cell therapy in a mouse model of Hutchinson-Gilford Progeria Syndrome (HGPS), a lethal childhood disorder for which no definitive therapy is available. HGPS patients have failure to thrive, lipodystrophy, skeletal dysplasia, sclerotic skin, alopecia, and occlusive vascular disease that results in premature death from myocardial infarction or stroke in early teens. In HGPS, the accumulation of incompletely processed nuclear architectural protein lamin A (a farnesylated version of prelamin A, termed progerin) results in dysfunction of multiple organ systems, particularly those of mesenchymal origin. Consistent with this, progerin has been shown to interfere with the proliferation and differentiation of mesenchymal stem cells (MSCs). Furthermore, MSC depletion is thought to account for the specific segmental nature of human progeria. The identification of HGPS-specific MSC dysfunction, and emerging evidence about the plasticity and paracrine effects of MSCs have prompted us to test the hypothesis that MSCs might be coaxed into becoming cells able to correct widespread pathology in HGPS. To determine whether MSCs can be used to rescue progeria phenotype, MSCs from wild-type donors were tested. First, donor MSCs (0.5 × 106 per recipient) were stably transfected to express the red fluoroform DsRed2, which permitted donor cell tracking in tissues post mortem. Next, to achieve wide biodistribution DsRed2+ MSCs were injected intra-arterially into 2-week-old ZMPSTE24−/− mutant mice. Like HGPS cells, ZMPSTE24−/− mutant mice accumulate progerin and the mice exhibit many progeria-like signs, including alopecia, micrognathia, dental abnormalities, osteolytic lesions in bones, osteoporosis, retarded growth, muscle weakness, and shortened lifespan. Therefore, survival, growth (measured by weight gain), and muscle weakness (measured by grip strength) were analyzed. MSC-treated (n = 13) versus untreated (n = 23) ZMPSTE24−/− mice had significantly increased

  • survival (65% versus 100%),

  • weight gain after 6 weeks of life, and

  • grip strength (judged by the ability to hang onto an upside–down grid).

These data are consistent with the hypothesis that the transfer of wild-type MSCs reduces the severity of the lamin A defect. To investigate whether the benefits associated with MSC infusion were attributable to persistent tissue engraftment or to a transient paracrine effect of donor MSCs, all mice were electively harvested at 20 weeks of age. Because dermal lipodystrophy, cardiac arteriosclerosis, and skeletal myopathy are prominent pathological findings in both human and murine progeria, post-mortem analyses focused on donor cell engraftment and progerin expression in corresponding organs of pathology (skin, liver, and skeletal muscle). Donor cells were identified in skin, liver, and skeletal muscle specimens with a frequency of 1%–5%, indicating that donor MSCs can repopulate tissue niches presumed to be dysfunctional in progeria. Experiments are ongoing to evaluate tissue levels of prelamin A and mature lamin A, abnormalities in nuclear shape, and pertubations in intracellular signaling pathway genes known to be dysregulated in human progeria. Collectively, these data demonstrate the proof of principle of MSC transfer for phenotypic reversion of lamin A defect in murine progeria. This may offer a valuable approach for treatment of human HGPS with human MSCs, which are already in clinical use.

Disclosures: No relevant conflicts of interest to declare.

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