Stm Clls and Clonng: Adancs and Applcatons 2010:3
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Applcaton of SCs n ALS
Cu/Zn superoxide dismutase-1 (SOD-1) proteins modulatesequestration o neurolament mRNAs in the aggregatescharacteristic in ALS MN degeneration.
Mutations in a gene encoding another DNA/RNA-binding protein with striking structural and unctional similarities toTDP-43 named FUS (used in sarcoma) or TLS (transloca-tion in liposarcoma) have been recently reported to trigger degeneration o MNs
and be responsible or FTD.
Although this gene was initially identied as a componento a usion pro-oncogene resulting rom a chromosomaltranslocation seen in liposarcomas, it belongs similarly to asubamily o RNA-binding proteins, involved in MN (patho) physiological biology/metabolism (Figure 1B). Interestingly,FUS/TLS protein interacts with RNA, single-stranded DNA,and double-stranded DNA, and is involved in unique unc-tions in the mRNA processing and transport, transcriptionalregulation, and maintenance o genomic stability.
It has been also reported the selective presence o FUS
inclusionsin an elderly patient apparently not mutated in the gene butaected by MND.
The emerging scenario o multiple regional involve-ments due to the TDP-43/FUS neuropathological inclu-sions in the central nervous system (CNS) o ALS patientsentails a signicant impact on the therapeutic strategiesapplicable to them and, particularly, on the SC approach,since RNA-binding proteins appear as key regulators o signaling networks responsible or neuronal developmentand homeostasis,
as well as neural SC biology.
Thereore,healthy transplanted cells cross talk with the surroundingsmay also be compromised by the abnormal cellular RNAmetabolism, able to trigger MN degeneration, thus imped-ing any therapeutic outcomes. FUS and TDP-43 harbor alsoa “prion domain” very similar to the specic one present inseveral yeast prion proteins prone to pathological misoldingtransmissible within or between healthy cells or species. Inthis case, no SC strategy could maintain positive therapeuticoutcomes in the long term, without a supportive treatmentable to prevent the spread o the disease.
Moreover, merecell substitution appears insucient to contrast all the altera-tions in the interrelated complex pathways activated by ALS,as described in the ollowing paragraphs.
Stem cells and newpharmacotherapeutic strategies:approaching novel genes, diseasemodeling, and drug candidates
Additional interesting hints derive rom the discovery o thenovel pathological genes
sincethey also have led to the derivation o new animal models,alternatives to the classic transgenic (tg) SOD-1, or deci- phering the mechanisms responsible or the motor systemneurodegeneration with large implications or SC therapiesin the CNS
(Figure 1C). In particular, it appears thatTDP-43 plays a pivotal role in many orms o MND, and this protein, being implicated in some orms o dementia,exerts a contributory role in a wider number o neurodegen-erative diseases.
Moreover, a careul examination o the pathological SCs in these new animal models, as well as o the surrounding niche, could reveal abnormalities that mayinfuence reparative mechanisms, as already suggested intgSOD-1 NPs,
and in the bone marrow o sporadic ALS patients.
Furthermore, remarkable pieces o inormation areexpected rom the recent generation o iPS cells (induced pluripotent SCs, obtained by transducing cells with 4transcription actors: Oct-4, Sox2, Kl-4, and c-Myc;Figure 1D), deriving rom somatic tissues o an elderlyALS patient, which could be successully dierentiated toward well-characterized MNs.
iPS cells possess thesame advantages as traditional SCs due to their ability to produce dierentiated aected cells, such as neurons.
However, the use o oncogenes and retrovirus in the currentiPS cell establishment protocol raises saety concerns sincetheir progeny show high teratoma-orming propensitiesthat actually restricts their potential use in cell therapy.
Nevertheless, neurodegenerative disease-specic iPS may be used or assays with cell specimens uncollectible romlive patients (such as MNs, glial cells, and so on) to dis-sect their distinct peculiar infuence on pathological events(Figure 1E) and to dene new drug targets
(Figure 1F).Although reprogramming adult patient cells would be particularly interesting or both ALS and sALS, so ar noALS iPS-derived MNs appear to be aected by the disease.Conversely, both iPS cells rom spinal muscular atrophy
(SMA) and amiliar dysautonomia,
characterized bychildhood onset, recapitulate all the pathological selectivedecits. Thereore, it appears that the complex interactions between genetic and environmental eatures combined tosenescence processes,
which are completely lacking duringiPS-derived MN dierentiation, may play a key role in ALSlate-onset degeneration. Additional long-term studies would be necessary to recreate the correct pathophysiologicalconditions beore validation o this model or drug screeningor as a disease model or ALS.A precise dissection o the synergistic eects o SCimplantation on the ALS surroundings is limited by the