Induced pluripotent stem cells derived from mouse models of lysosomal storage disorders

Abstract

Most lysosomal storage diseases (LSDs) are life-threatening genetic diseases. The pathogenesis of these diseases is poorly understood. Induced pluripotent stem (iPS) cell technology offers new opportunities for both mechanistic studies and development of stem cellbased therapies. Here we report the generation of disease-specific iPS cells from mouse models of Fabry disease, globoid cell leukodystrophy (GLD), and mucopolysaccharidosis VII (MPSVII). These mouse model-derived iPS cells showed defects in disease-specific enzyme activities and significant accumulation of substrates for these enzymes. In the lineage-directed differentiation studies, Fabry-iPS and GLD-iPS cells were efficiently differentiated into disease-relevant cell types, such as cardiomyocytes and neural stem cells, which might be useful in mechanistic and therapeutic studies. Notably, MPSVII-iPS cells demonstrated a markedly impaired ability to form embryoid bodies (EBs) in vitro. MPSVII-EBs exibited elevated levels of hyaluronan and its receptor CD44, and markedly reduced expression levels of E-cadherin and cell-proliferating marker. Partial correction of enzyme deficiency in MSPVII-iPS cells led to improved EB formation and reversal of aberrant protein expression. These data indicate a potential mechanism for the partial lethality of MPSVII mice in utero, and suggest a possible abnormality of embryonic development in MPSVII patients. Thus, our study demonstrates the unique promise of iPS cells for studying the pathogenesis and treatment of LSDs.cardiomyocyte | embryoid body | neural stem cell

The Current Status of iPS Cells in Cardiac Research and Their Potential for Tissue Engineering and Regenerative Medicine

“…Most iPS cells derived from human [12, 15, 16, 35, 38, 44, 57, 58] or murine [8, 14, 27, 35, 44, 53, 58, 59] origin. It has been shown that iPS cells can be generated from a variety of cell types, which differ in terms of mutational burden, relicative potential in vitro, availability, accessibility, and reprogramming efficiency.…”

“…It is associated with severe multisystem abnormalities including cardiac hypertrophy and stroke. Meng et al [59] investigated the generation and characterization of iPS cells from mouse models of Fabry disease.…”

Hematopoietic differentiation of induced pluripotent stem cells from patients with mucopolysaccharidosis type I (Hurler syndrome)

“…Recently iPS cells from several mouse models of lysosomal storage disorders have been described, 40 but induction of iPS cells from human cells has been reported to date for only one human lysosomal storage disorder, type III Gaucher disease. 27 There are Ն 2 potential critical advantages of HSC derivation from genetically corrected iPS cells instead of gene correction of autologous HSCs.…”

Cell-and Gene-based Therapeutic Approaches for Neurological Deficits in Mucopolysaccharidoses

“…The ability to obtain stem cells specific to an individual offers new prospects for regenerative medicine in general, and also open a door for autologous stem cell-based gene therapy in neuropathic MPS in particular. In fact, generation of murine iPS cells tailored to MPS VII mouse has been reported using primary MPS VII fibroblasts isolated from tail-clips [70]. While this new class of stem cells may provide opportunities to develop patient-specific pluripotent cell lines for cell-based CNS therapies, substantial research and developments are still required for their ultimate usage in clinics.…”