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  • Silmitasertib Parkinson s disease PD is

    2018-10-26

    Parkinson\'s disease (PD) is a neurological disorder characterized by the degeneration of dopaminergic neurons in the midbrain substantia nigra, leading to a reduction of dopamine in the striatum (Gaillard and Jaber, 2011). Currently, dopaminergic neurons can be obtained through differentiation from pluripotent Silmitasertib (Ganat et al., 2012). Recently, the direct conversion of fibroblasts also generates personalized induced dopaminergic neurons (Pfisterer et al., 2011; Caiazzo et al., 2011; Liu et al., 2012b; Kim et al., 2011b). However, the terminally differentiated induced neurons are not adequate for transplantation (Rhee et al., 2011). Progenitors or precursors should be advantageous in handling and obtaining the cells in vitro as well as in proper integration in vivo. Thus, we hypothesized that dopaminergic progenitors/precursors (DPs) also can be generated by direct lineage reprogramming. As the PDR approach can generate proliferating neural stem cells (NSCs) under appropriate environmental conditions (Liu et al., 2012a; Kim et al., 2011a; Wang et al., 2012; Thier et al., 2012; Han et al., 2012; Lu et al., 2013), we assumed that DPs, which are further specified than general NSCs but not fully differentiated into neurons, can be generated under appropriately modified environmental conditions by PDR. Here, we showed that mouse fibroblasts can be directly reprogrammed into midbrain-specific DPs through the transient expression of the four Yamanaka factors under dopaminergic neuron-specific and intermediate cell-enriching conditions. This work demonstrates direct cell fate alteration from fibroblast to specific neural progenitors through PDR strategy and provides another novel route for obtaining useful progenitors for potential therapies and studies on various neural diseases.
    Materials and methods
    Results and discussion
    Conclusions Recently, several groups reported direct conversion of fibroblasts into dopaminergic neurons (Pfisterer et al., 2011; Caiazzo et al., 2011; Liu et al., 2012b; Kim et al., 2011b), where the resulting cells are non-proliferating terminally differentiated neurons. We demonstrated here that mouse fibroblasts can be directly reprogrammed to functional and proliferating midbrain DPs through cell activation by pluripotency factors and directed specification by signal factors including SHH and FGF8. The trajectory of iDP reprogramming is traced as different from iNSC reprogramming. We were able to finely tune the process to increase the efficiency by co-inhibition of Jak and Gsk3β. The iDPs are functional and proliferating progenitors which give rise to typical midbrain dopaminergic neurons. We expect that our PDR strategy is not only applicable for iDP generation but also for direct lineage reprogramming to other progenitors which are required for various neural diseases. The following are the supplementary data related to this article.
    Author contributions
    Acknowledgments This work was supported by grants through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-020272(3), 2012M3A9C7050224, NRF-2012R1A1A2043433, and 2011-0014893), and the KRIBB/KRCF research initiative program (NAP-09-3). We thank Dr. Sheng Ding in Gladstone Institute of Cardiovascular Disease for generous gifts of reprogrammable cells and vector.
    Introduction The blood vessel and hematopoietic systems are the first functional organs formed in the developing embryo. Endothelial cells are initially generated through vasculogenesis to produce a primitive vascular plexus. Subsequent angiogenesis lead to the expansion and remodelling of this initial endothelial network (Patan, 2004). The newly formed endothelial vessels become rapidly associated with mural cells of the smooth muscle cell lineage. These cells are either referred to as vascular smooth muscle cells if they encircle larger vessels or as pericytes if they reside within the wall of small vessels Silmitasertib such as capillaries and post-capillary venules. These cells regulate blood flow through contraction and have also been proposed to control endothelial cell proliferation and differentiation by direct signalling and deposition of extracellular matrix (Betsholtz et al., 2005). Hampered smooth muscle cell differentiation or function results in severe vascular defects such as abnormal vessel morphology and increased permeability leading to a number of cardiovascular disorders including congenital heart diseases, aortic aneurysm, atherosclerosis, hypertension, and restenosis (Carvalho et al., 2004; Guo et al., 2007; Hellstrom et al., 2001, 1999; Lindahl et al., 1997; Milewicz et al., 2008; Zhu et al., 2006). In Hutchinson–Gilford progeria syndrome, loss of smooth muscle cells has been suggested to lead to progressive arterial occlusion that causes death from myocardial infarction or from stroke at an average age of thirteen years (Varga et al., 2006).