Mitsuhiro Morita

Identification and characterization of PDGFRα+ mesenchymal progenitors in human skeletal muscle.

Fatty and fibrous connective tissue formation is a hallmark of diseased skeletal muscle and deteriorates muscle function. We previously identified non-myogenic mesenchymal progenitors that contribute to adipogenesis and fibrogenesis in mouse skeletal muscle. In this study, we report the identification and characterization of a human counterpart to these progenitors. By using PDGFRα as a specific marker, mesenchymal progenitors can be identified in the interstitium and isolated from human skeletal muscle. PDGFRα+ cells represent a cell population distinct from CD56+ myogenic cells, and adipogenic and fibrogenic potentials were highly enriched in the PDGFRα+ population. Activation of PDGFRα stimulates proliferation of PDGFRα+ cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα+ cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. Our results revealed the pathological relevance of PDGFRα+ mesenchymal progenitors to human muscle diseases and provide a basis for developing therapeutic strategy to treat muscle diseases.

Cementless total hip replacement: past, present, and future

Cementless total hip replacement (THR) is rapidly being accepted as the surgery for arthritic diseases of the hip joint. The bone-ingrowth rate in porous-type cementless implants was about 90% over 10 years after surgery, showing that biological fixation of cementless THR was well maintained on both the stem and cup sides. As for the stress shielding of the femur operated using a distal fixation-type stem, severe bone resorption was observed. The severe bone resorption group showed continuous progression for more than 10 years after surgery. Stem loosening directly caused by stress shielding has been considered less likely; however, close attention should be paid to bone resorption-associated disorders including femoral fracture. Cementless cups have several specific problems. It is difficult to decide whether a cup should be placed in the physiological position for the case of acetabular dysplasia by bone grafting or at a relatively higher position without bone grafting. The bone-ingrowth rate was lower in the group with en bloc bone grafting, and the reactive line was frequently noted in the bone-grafted region. Although no data indicated that en bloc bone grafting directly led to poor outcomes, such as loosening, cup placement at a higher site without bone grafting is now selected by most operators. The polyethylene liner in a cementless cup is thinned due to the metal cup thickness; however, it has been suggested that the apparent relation between the cup size and the wear rate was absent as long as a cementless cup is used. Comparative study indicated cementless THR was inferior with regard to the yearly polyethylene wear rate and incidence of osteolysis on both the stem and cup sides. Meta-analysis study on the survival rate between cement and cementless THR reported that cemented THR was slightly superior. It should be considered that specific problems for cementless THR, especially with regard to polyethylene wear, do occur.

Cell-Surface Protein Profiling Identifies Distinctive Markers of Progenitor Cells in Human Skeletal Muscle

Summary Skeletal muscle contains two distinct stem/progenitor populations. One is the satellite cell, which acts as a muscle stem cell, and the other is the mesenchymal progenitor, which contributes to muscle pathogeneses such as fat infiltration and fibrosis. Detailed and accurate characterization of these progenitors in humans remains elusive. Here, we performed comprehensive cell-surface protein profiling of the two progenitor populations residing in human skeletal muscle and identified three previously unrecognized markers: CD82 and CD318 for satellite cells and CD201 for mesenchymal progenitors. These markers distinguish myogenic and mesenchymal progenitors, and enable efficient isolation of the two types of progenitors. Functional study revealed that CD82 ensures expansion and preservation of myogenic progenitors by suppressing excessive differentiation, and CD201 signaling favors adipogenesis of mesenchymal progenitors. Thus, cell-surface proteins identified here are not only useful markers but also functionally important molecules, and provide valuable insight into human muscle biology and diseases.

Promethazine Hydrochloride Inhibits Ectopic Fat Cell Formation in Skeletal Muscle

Fatty degeneration of skeletal muscle leads to muscle weakness and loss of function. Preventing fatty degeneration in skeletal muscle is important, but no drug has been used clinically. In this study, we performed drug repositioning using human platelet-derived growth factor receptor α (PDGFRα)-positive mesenchymal progenitors that have been proved to be an origin of ectopic adipocytes in skeletal muscle. We found that promethazine hydrochloride (PH) inhibits adipogenesis in a dose-dependent manner without cell toxicity. PH inhibited expression of adipogenic markers and also suppressed phosphorylation of cAMP response-element binding protein, which was reported to be a primary regulator of adipogenesis. We established a mouse model of tendon rupture with intramuscular fat deposition and confirmed that emerged ectopic adipocytes are derived from PDGFRα+ cells using lineage tracing mice. When these injured mice were treated with PH, formation of ectopic adipocytes was suppressed significantly. Our results show that PH inhibits PDGFRα+ mesenchymal progenitor-dependent ectopic adipogenesis in skeletal muscle and suggest that treatment with PH can be a promising approach to prevent fatty degeneration of skeletal muscle.