Tissue-Engineered Skeletal Muscle Organoids for Reversible Gene Therapy

Vandenburgh, Herman H.; Tatto, Michael Del; Shansky, Janet; Lemaire, Julie; Chang, Albert Y.; Payumo, Francis; Lee, Peter; Goodyear, Amy; Raven, Latasha

doi:10.1089/hum.1996.7.17-2195

Cited by 136 publications

(115 citation statements)

References 26 publications

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“…A number of recent studies have found that passive tension can be attributed to the cells' acting on the gel to generate the passive forces (7,9). The primary human muscle cells used in the present work caused gel contraction and dehydration as previously observed with avian and rodent muscle cells (38,40). This suggests that HBAMs are under passive tension in their normal tissue-cultured state.…”

Section: Discussionsupporting

confidence: 73%

Mechanical stimulation improves tissue-engineered human skeletal muscle

Powell

Smiley

Mills

et al. 2002

American Journal of Physiology-Cell Physiology

402

386

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Human bioartificial muscles (HBAMs) are tissue engineered by suspending muscle cells in collagen/MATRIGEL, casting in a silicone mold containing end attachment sites, and allowing the cells to differentiate for 8 to 16 days. The resulting HBAMs are representative of skeletal muscle in that they contain parallel arrays of postmitotic myofibers; however, they differ in many other morphological characteristics. To engineer improved HBAMs, i.e., more in vivo-like, we developed Mechanical Cell Stimulator (MCS) hardware to apply in vivo-like forces directly to the engineered tissue. A sensitive force transducer attached to the HBAM measured real-time, internally generated, as well as externally applied, forces. The muscle cells generated increasing internal forces during formation which were inhibitable with a cytoskeleton depolymerizer. Repetitive stretch/relaxation for 8 days increased the HBAM elasticity two- to threefold, mean myofiber diameter 12%, and myofiber area percent 40%. This system allows engineering of improved skeletal muscle analogs as well as a nondestructive method to determine passive force and viscoelastic properties of the resulting tissue.

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Section: Discussionsupporting

confidence: 73%

Mechanical stimulation improves tissue-engineered human skeletal muscle

Powell

Smiley

Mills

et al. 2002

American Journal of Physiology-Cell Physiology

402

386

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“…When implanted in nonmuscle or muscle sites, they survive long-term and deliver predictable levels of gene products, such as growth hormone, insulin-like growth factors, and erythropoietin for months. 10,11 In the present study, we show that BAMs genetically modified to secrete recombinant VEGF can also stimulate localized angiogenesis in a predictable dose-dependent manner. Human BAMs delivering angiogenic or arteriogenic factors could be useful in treating a range of cardiovascular diseases.…”

supporting

confidence: 57%

Recombinant Vascular Endothelial Growth Factor Secreted From Tissue-Engineered Bioartificial Muscles Promotes Localized Angiogenesis

Shansky

Tatto

et al. 2001

Circulation

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Background Therapeutic angiogenesis by the administration of recombinant vascular endothelial growth factor (rVEGF) is a novel strategy for the treatment of ischemic disorders. rVEGF has been delivered as a protein, by plasmid DNA, and by genetically engineered cells with different pharmacokinetic and physiological properties. In the present study, we examined a new method for delivery of rVEGF using implantable bioartificial muscle (BAM) tissues made from genetically modified primary skeletal myoblasts. Our goal was to determine whether the rVEGF delivered by this technique promoted controlled angiogenesis in nonischemic and/or ischemic adult mouse tissue. Methods and Results Primary adult mouse myoblasts were retrovirally transduced to secrete human or mouse rVEGF and tissue-engineered into implantable 1×10 to 15-mm BAMs containing parallel arrays of postmitotic myofibers. In vitro, they secreted 290 to 511 ng of bioactive mouse or human VEGF/BAM per day. rVEGF BAMs implanted subcutaneously into syngeneic mice caused a 30-fold increase in the number of CD31-positive capillary cells within the BAM by 1 week compared with control BAMs. Implantation of rVEGF-secreting BAMs into ischemic hindlimbs resulted in a 2- to 3-fold increase in capillary density of neighboring host muscle by 1 week and out to 4 weeks with no evidence of hemangioma formation. Conclusions Local delivery of rVEGF from BAMs rapidly increases capillary density both within the BAM itself and in adjacent ischemic muscle tissue. Genetically engineered muscle tissue provides a method for therapeutic protein delivery in a dose-regulated fashion.

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“…As previously described, 22,23 BAM troughs were made using silicone tubing (Nalgene), split longitudinally with tiny sections of silicone sheets (Nalgene) that were glued to the open ends of the tubing with RTV silicone adhesive (GE). Small stainless steel minutien pins (Fine Science Tools) held Velcro tabs at the ends of the mold to act as attachment sites for the collagen/matrigel construct, and over time, to maintain passive tension.…”

Section: Bioartificial Muscle Assemblymentioning

confidence: 99%

Effect of MicroRNA Modulation on Bioartificial Muscle Function

Rhim

Cheng

Kraus

et al. 2010

Tissue Engineering Part A

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Cellular therapies have recently employed the use of small RNA molecules, particularly microRNAs (miRNAs), to regulate various cellular processes that may be altered in disease states. In this study, we examined the effect of transient muscle-specific miRNA inhibition on the function of three-dimensional skeletal muscle cultures, or bioartificial muscles (BAMs). Skeletal myoblast differentiation in vitro is enhanced by inhibiting a proliferationpromoting miRNA (miR-133) expressed in muscle tissues. As assessed by functional force measurements in response to electrical stimulation at frequencies ranging from 0 to 20 Hz, peak forces exhibited by BAMs with miR-133 inhibition (anti-miR-133) were on average 20% higher than the corresponding negative control, although dynamic responses to electrical stimulation in miRNA-transfected BAMs and negative controls were similar to nontransfected controls. Immunostaining for alpha-actinin and myosin also showed more distinct striations and myofiber organization in anti-miR-133 BAMs, and fiber diameters were significantly larger in these BAMs over both the nontransfected and negative controls. Compared to the negative control, anti-miR-133 BAMs exhibited more intense nuclear staining for Mef2, a key myogenic differentiation marker. To our knowledge, this study is the first to demonstrate that miRNA mediation has functional effects on tissue-engineered constructs.

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Tissue-Engineered Skeletal Muscle Organoids for Reversible Gene Therapy

Cited by 136 publications

References 26 publications

Mechanical stimulation improves tissue-engineered human skeletal muscle

Mechanical stimulation improves tissue-engineered human skeletal muscle

Recombinant Vascular Endothelial Growth Factor Secreted From Tissue-Engineered Bioartificial Muscles Promotes Localized Angiogenesis

Effect of MicroRNA Modulation on Bioartificial Muscle Function

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