Transplantation of Normal and DMD Myoblasts Expressing the Telomerase Gene in SCID Mice

Seigneurin-Venin, Sophie; Bernard, V; Moisset, Pierre Alain; Ouellette, Michel; Mouly, Vincent; Donna, S. Di; Wright, Woodring E.; Tremblay, Jacques P.

doi:10.1006/bbrc.2000.2735

Cited by 22 publications

(8 citation statements)

References 31 publications

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“…As regards immortalization, cells lacking T/t-Ag entered a permanent growth arrest between population doublings 13 and 15 with morphologic features consistent with senescence ( Fig. 1C; uninfected, M-VVV, M-VHV), in agreement with the results of others (27). The stable expression of H-Ras V12G alone or in combination with hTERT resulted in cell death ( Fig.…”

Section: Resultssupporting

confidence: 89%

Genetic Modeling of Human Rhabdomyosarcoma

Linardic¹,

Downie²,

Qualman

et al. 2005

Cancer Research

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Rhabdomyosarcoma, a malignancy showing features of skeletal muscle differentiation, is the most common soft tissue sarcoma of childhood. The identification of distinct clinical presentation patterns, histologic tumor types, and risk groups suggests that rhabdomyosarcoma is a collection of highly related sarcomas rather than a single entity. In an effort to understand this seemingly heterogeneous malignancy, we constructed a genetically defined but malleable model of rhabdomyosarcoma by converting less differentiated human skeletal muscle cell precursors (SkMC) and committed human skeletal muscle myoblasts (HSMM) into their malignant counterparts by targeting pathways altered in rhabdomyosarcoma. Whereas the two cell types were both tumorigenic, SkMCs gave rise to highly heterogeneous tumors occasionally displaying features of rhabdomyosarcoma, whereas HSMMs formed rhabdomyosarcoma-like tumors with an embryonal morphology, capable of invasion and metastasis. Thus, despite introducing the same panel of genetic changes, altering the skeletal muscle cell of origin led to different tumor morphologies, suggesting that cell of origin may dictate rhabdomyosarcoma tumor histology. The ability to now genetically induce human rhabdomyosarcoma-like tumors provides a representative model to dissect the molecular mechanisms underlying this cancer. (Cancer Res 2005; 65(11): 4490-5)

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Section: Resultssupporting

confidence: 89%

Genetic Modeling of Human Rhabdomyosarcoma

Linardic¹,

Downie²,

Qualman

et al. 2005

Cancer Research

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“…Thomas et al (5) reported on the first use of hTERT expression in xenotransplantion by using bovine adrenocortical cells implanted into severe combined immunodeficient mice to rescue organ function after adrenalectomy. hTERT lifespan extension is also being investigated for the treatment of Duchenne muscular dystrophy by using genetically modified muscle satellite cells (6,7). Other cell types that have been lifespan-extended by telomerase in anticipation of tissue engineering applications include retinal pigment epithelia (8)(9)(10)(11)(12), dermal fibroblasts (13,14), vascular endothelium (15)(16)(17), bone marrow stromal cells (18)(19)(20)(21), osteoblasts (22,23), mesenchymal stem cells (24), and hepatic stellate cells (25,26).…”

mentioning

confidence: 99%

Relevance and safety of telomerase for human tissue engineering

Klinger

Blum

Hearn

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Tissue engineering holds the promise of replacing damaged or diseased tissues and organs. The use of autologous donor cells is often not feasible because of the limited replicative lifespan of cells, particularly those derived from elderly patients. Proliferative arrest can be overcome by the ectopic expression of telomerase via human telomerase reverse transcriptase (hTERT) gene transfection. To study the efficacy and safety of this potentially valuable technology, we used differentiated vascular smooth muscle cells (SMC) and vascular tissue engineering as a model system. Although we previously demonstrated that vessels engineered with telomerase-expressing SMC had improved mechanics over those grown with control cells, it is critical to assess the phenotypic impact of telomerase expression in donor cells, because telomerase upregulation is observed in >95% of human malignancies. To study the impact of telomerase in tissue engineering, expression of hTERT was retrovirally induced in SMC from eight elderly patients and one young donor. In hTERT SMC, significant lifespan extension beyond that of control was achieved without population doubling time acceleration. Karyotype changes were seen in both control and hTERT SMC but were not clonal nor representative of cancerous change. hTERT cells also failed to show evidence of neoplastic transformation in functional assays of tumorigenicity. In addition, the impact of donor age on cellular behavior, particularly the synthetic capability of SMC, was not affected by hTERT expression. Hence, this tissue engineering model system highlights the impact of donor age on cellular synthetic function that appears to be independent of lifespan extension by hTERT.tumorigenicity ͉ smooth muscle cells ͉ vascular graft

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“…Some possibilities studied to avoid this problem were to immortalize the DMD myoblasts with the thermolabile tsA58 mutant of SV40 large-T antigen [213] or by genetically restoring the telomerase activity [214,215]. One possibility to circumvent this problem would be to use some of the myogenic cells described above as "heterodox, " provided that these other cells can be efficient for transplantation in humans.…”

Section: Experimental Strategies To Avoid Acute Rejection: Autotranspmentioning

confidence: 99%

Cell Transplantation and “Stem Cell Therapy” in the Treatment of Myopathies: Many Promises in Mice, Few Realities in Humans

Skuk

2013

ISRN Transplantation

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Myopathies produce deficits in skeletal muscle function and, in some cases, progressive and irreversible loss of skeletal muscles. The transplantation of myogenic cells, that is, cells able to differentiate into myofibers, is an experimental strategy for the potential treatment of some of these diseases. The objectives pursued by the transplantation of these cells are essentially three: (a) the fusion with the patient's myofibers to obtain the expression of therapeutic proteins into them, (b) the neoformation of new functional myofibers in skeletal muscles that were too degenerated by the progressive degeneration, and (c) the formation of a new pool of healthy donor-derived satellite cells. Although the repertoire of myogenic cells appears to have expanded in recent years, myoblasts are the only cells that have been demonstrated to engraft in humans. The present work aims to make a comprehensive review of the subject, from its beginnings to recent advances, including the preclinical experience in different animal models and recent clinical findings.

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Transplantation of Normal and DMD Myoblasts Expressing the Telomerase Gene in SCID Mice

Cited by 22 publications

References 31 publications

Genetic Modeling of Human Rhabdomyosarcoma

Genetic Modeling of Human Rhabdomyosarcoma

Relevance and safety of telomerase for human tissue engineering

Cell Transplantation and “Stem Cell Therapy” in the Treatment of Myopathies: Many Promises in Mice, Few Realities in Humans

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