Abstract
Type 6 collagen (COL6) is produced by mesenchymal stromal cells (MSC) in skeletal muscle, and its gene mutation is the cause of Ullrich congenital muscular dystrophy (UCMD). To test whether COL6 supplementation has a therapeutic effect for UCMD, we conducted in vivo and in vitro experiments using healthy induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) and COL6-deficient iMSCs (KO-iMSCs). The transplantation of these iMSCs or primary MSCs into the skeletal muscle of immunodeficient UCMD model mice demonstrated that muscle regeneration and maturation were promoted only in the region supplemented with COL6. In addition, co-culture experiments of skeletal muscle satellite cells derived from UCMD model mice (Col6a1KO-MuSCs) showed iMSCs but not KO-iMSCs could improve the proliferation, differentiation, and maturation of Col6a1KO-MuSCs. These findings indicate that COL6 supplementation improves muscle regeneration and maturation in UCMD model mice and will help elucidate the pathology of UCMD and establishment of effective treatments.
Highlights
Mesenchymal stromal cells (MSCs) function as supportive cells on skeletal muscle homeostasis through several secretory factors including type 6 collagen (COL6)
COL6A1 mRNA was highly expressed in primary MSCs (pMSCs) and iMSCs, but barely in induced pluripotent stem cell (iPSC) or KO-iMSCs (Figure 1a)
The whole CSA and muscle wet weight of iMSC- and pMSC-transplanted TA muscles increased compared with Col6a1KO muscles, whereas KO-iMSC-transplanted TA muscles showed no difference with Col6a1KO muscle (Figure S5b, c). These results indicated that Type 6 collagen (COL6) supplementation by COL6producing pMSCs/iMSCs increased the muscle fiber diameter in Col6a1KO TA muscle
Summary
Mesenchymal stromal cells (MSCs) function as supportive cells on skeletal muscle homeostasis through several secretory factors including type 6 collagen (COL6). Patient biopsies revealed a deficiency of type 6 collagen (COL6) in the muscles, and later it was found that COL6A1, COL6A2, and COL6A3 mutations cause defective extracellular microfibril assembly [3,4,5]. COL6 is a fibril molecule with a molecular weight of about 500 kDa and is widely distributed in the extracellular matrix (ECM) of systemic tissues including skeletal muscle [6,7,8,9]. It interacts with fibrous collagen such as collagen 1 and many kinds of ECM and basement membrane proteins [10,11,12]. COL6 deficiency alters the ECM structure and biomechanical properties and leads to mitochondrial defects [25,26,27,28,29,30], decreased autophagy [31,32,33], and impaired muscle regeneration [34, 35]
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