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Regeneration and transdifferentiation of skeletal muscle

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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Regeneration and transdifferentiation of skeletal muscle

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Dr. PéterBalogh and Dr. Péter Engelmann Transdifferentiation and regenerative medicine – Lecture 7 Regeneration and transdifferentiation of skeletalmuscle

  3. Conditions requiring skeletal muscle regeneration • Injury leading to extensive muscle damage • Inherited diseases – Duchenne’s muscular dystrophy: • X-linked mutation of dystrophin gene • 1:3500 males affected • Dystrophin (2.4 Mb in size) is the largest known mammalian gene • Onset of the disease: DMD-afflicted patients are diagnosed in childhood. The progressive muscle-wasting disease affects striated muscle including limb muscles, diaphragm, and heart leading to cardiorespiratory failure, and death usually occurs in the teenage years or early 20s.

  4. Experimental models for studying muscle regeneration • Mdx mice: spontaneous mutation of the distrophin gene (variable severities in different inbred mouse strains) • Distrophin/utrophin double mutant mouse • Canine X-linked muscular dystrophy (cxmd) is the best representation of DMD, but the phenotype is variable.

  5. Embyonicdevelopment of skeletalmuscle DT Myf5 NT DT Pax3/ Pax7 MT SC SC MyoD VLL Limb NC Pax3 Myf5 Myf6 Bmp4 Nog Nog MyoD Wnt11 Wnt1/3 Myf5 Myogenesis Myogn Myf6, MyoD Pax3 Shh Wnt7a MyoD

  6. Transcriptional control of myogenic differentiation Injury Fusion Differentiation Maturation Myofiber nuclei Satellite cell (quiescent) Proliferation and self-renewalof satellite cells Regenerating myofiber nuclei Satellite cell (quiescent) Quiescent Activation/Proliferation Differentiation Myogenic stem cell (MSC) Myogenic progenitor cells (MPC) Myoblast Myotube Transit Amplifying cells Cd34 Cdh15 Foxk1 Met Pax3 Pax7 Sox8 Sdc4 Sox15 Vcam1 Myf5 Myf6 MyoD Des Myog

  7. Cellular sources for muscle regeneration • Satellite cells and their precursors • Endothelial cells associated with embryonic limb muscles • Mesangioblasts • Bone marow-derived stem cells • Pluripotent cells found within muscle-derived side population (SP) cells • Highly active Mdr-dependent expulsion of Hoechst 33342 dye

  8. Tissuesourcesformuscleregeneration Interstitialcells Satellite cell Vascularprogenitors Myofiber nuclei Bonemarrowcells

  9. Muscle stem cells – satellite cells • The satellite cells reside beneath the basal lamina of muscle, closely juxtaposed to muscle fibers • Approximately up 2–7% of the nuclei associated with a particular fiber • Heterogeneous composition: fusing/non-fusing subsets • Ontogeny: somite/perivascular cells expressing Pax3/Pax7 • Surface markers • Mouse: M-cadherin, CD34, VCAM, CD56, c-met (HGF-receptor) • Human: CD56

  10. Structure and regeneration of skeletal muscle Myofibril Quiescent SC Pax7+ Hematopoietic cells Activation Return to quiescence Activated SC Pax7+ Myf5+MyoD+ Basal lamina Pericyte Asymmetric division Satellite cell (SC) Myoblast Pax7- Myf5+MyoD+ Endothelial cell Myonucleus Expansion (symmetric division) Interstitial cell Arteriole and capillaries Fusion and differentiation Muscle fiber Myocyte MyoD+

  11. Kinetics of musclerepair Maturation Differentiation Proliferation Activation 0 1 2 5 10 14 Days post injury

  12. Problems with myoblast regeneration in Duchenne’s muscular distrophy • Necessity for immunosuppression • Immunosuppressant drugs cause myoblast apoptosis • Short migratory distance following intramuscular injection – 100 injections/cm2 (totalling up to 4,000 injections in a single patient!)

  13. Non-SCs contributing to muscle regeneration MABs/pericytes Myoendothelialcells EPCs MSCs Dermisorothertissues Vessels Reprogramming HSCs Sidepopulation CD133+stemcells Blood iPS cells SCs and subpopulations MDSCs CD133+ stem cells Skeletal muscle Characterization Mesenchymal differentation HSCs Side population Mesenchymal stem cells MAPCs Bone marrow Adipose-derived stem cells MyoD-converted cells Other sources Expansion Autologoustransplantation (aftergeneticcorrection) Allogeneictransplantation Commitment(ifneeded)

  14. Summary • The prime candidates for skeletal muscle regeneration are the satellite cells, but cells from other sources (embryonic as well as non-embryonic) may also associate/promote the process. • Muscle regeneration is accomplished through (a) promoting vascular repair, (b) cellular differentiation from muscle stem cells and (c) possible transdifferentiation.

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