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Marti M
,
Montserrat N
,
Pardo C
,
Mulero L
,
Miquel-Serra L
,
Rodrigues AM
,
Andrés Vaquero J
,
Kuebler B
,
Morera C
,
Barrero MJ
,
Izpisua Belmonte JC
.
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Adult muscle stem cells and their committed myogenic precursors, commonly referred to as the satellite cell population, are involved in both muscle growth after birth and regeneration after damage. It has been previously proposed that, under these circumstances, satellite cells first become activated, divide and differentiate, and only later fuse to the existing myofiber through M-cadherin-mediated intercellular interactions. Our data show that satellite cells fuse with the myofiber concomitantly to cell division, and only when the nuclei of the daughter cells are inside the myofiber, do they complete the process of differentiation. Here we demonstrate that M-cadherin plays an important role in cell-to-cell recognition and fusion, and is crucial for cell division activation. Treatment of satellite cells with M-cadherin in vitro stimulates cell division, whereas addition of anti-M-cadherin antibodies reduces the cell division rate. Our results suggest an alternative model for the contribution of satellite cells to muscle development, which might be useful in understanding muscle regeneration, as well as muscle-related dystrophies.
Fig. 1.
Dystrophin is undetectable in the contact zone between the myofiber and dividing satellite cells. (A) Xenopus body musculature stage 54. PCNA-positive cell (red) over a region without dystrophin (cyan). Insert: detail of the dystrophin gap in the area of contact (small arrow in main image). Scale bar: 25 µm. (B) Xenopus tail stage 53 (3 days after tail amputation). pHH3 (red)-positive cell in close contact with the myofiber over a region without dystrophin (cyan). Insert: detail of the dystrophin gap in the contact area (small arrow in main image). Scale bar: 25 µm. (C) Mouse muscle 7 days after birth. Pax7 (green)-PCNA (red)-positive cell over undetectable dystrophin (cyan). Insert: detail of the dystrophin gap in the contact area (small arrow in main image). Scale bar: 10 µm. (D) Mouse muscle 30 days after birth. Pax7 (green)- PCNA (red)-positive cell over undetectable dystrophin (cyan). Insert: detail of the dystrophin gap in the contact area (small arrow in main image). Scale bar: 10 µm. (E) 3-month-old mouse muscle, 6 days after cardiotoxin-induced injury. Pax7 (green)- PCNA (red)-positive cell over undetectable dystrophin (cyan). Insert: detail of the dystrophin gap in the contact area (small arrow in main image). Scale bar: 25 µm. (F) Xenopus limb bud, stage 57. Area without a plasma membrane between the satellite cell chromosomes and the sarcomeres (arrow). Insert: lower magnification showing the chromosomes of the satellite cell and the area observed (small arrow). Scale bar: 0.2 µm. (G) Xenopus tail stage 53; 14 days after amputation. Contact area between one satellite cell and the myofiber, without a plasma membrane between them (arrow). Insert: lower magnification showing the chromosomes of the satellite cell and the area observed (small arrow). Scale bar: 0.2 µm. (H) Mouse muscle 7 days after birth. Area without a plasma membrane between the satellite cell cytoplasm and myofiber cytoplasm. Part of the myofiber cytoplasm, with a clear plasma membrane, surrounds the satellite cell (red arrow). Insert: lower magnification showing the chromosomes of the satellite cell and the area observed (small arrow). Scale bar: 0.5 µm.
Fig. S2. (A) Pax7, PCNA, and Mef2, positive and negative cell count in tissue sections of mice treated with Ab-1 and Ab-2 for 48
hours, and control mice legs. The graph shows the mean and standard deviation of 3 replicas in each group (* p≤0.05). (B) Growth
curve of the cells infected with the 4 different shMcad tested, and with the LV-shCtrol (C) Myogenic cells infected with LV-ShMcad-1
expressed less Mcad (red) between them than the ones infected with LV-ShCtrol, and with clear decrease in the number of Ki67+
positive cells (cyan) (D) Decrease value of the Mcad transcripts in the myogenic cells infected with LV-shMcad1 versus the cells
infected with the LVshCtrol. Analyses performed by means of RTq PCR (E) Pax7, PCNA, and Mef2, positive and negative cell count
in tissue sections of mice treated with LV-shMcad and LV-shCtrol for 48 hours, and control mice legs. The graph shows the mean
and standard deviation of 3 replicas in each group (* p≤0.05). (F)Pax7, PCNA, and Mef2 positive and negative cell count in tissue
sections of Xenopus treated with tunicamycin for 48 hours. The graph shows the mean and standard deviation of 4 replicas in each
group (* p≤0.05)..
