No abstract

Mesenchymal stem cells (MSCs) are adult stem cells with fibroblast-like morphology and isolated from the bone marrow via plastic adhesion. Their multipotency and immunoregulatory properties make MSCs possible therapeutic agents, and an increasing number of publications and clinical trials have highlighted their potential in regenerative medicine. However, the finite proliferative capacity of MSCs limits their scalability and global dissemination as a standardized therapeutic product. Furthermore, adult tissue provenance could constrain accessibility, impinge on cellular potency, and incur greater exposure to disease-causing pathogens based on the donor. These issues could be circumvented by the derivation of MSCs from pluripotent stem cells. In this paper, we review methods that induce and characterize MSCs derived from induced pluripotent stem cells (iPSCs) and introduce MSC applications to disease modeling, pathogenic mechanisms, and drug discovery. We also discuss the potential applications of MSCs in regenerative medicine including cell-based therapies and issues that should be overcome before iPSC-derived MSC therapy will be applied in the clinic.

The trimeric intracellular cation (TRIC) channels TRIC-A and TRIC-B localize predominantly to the endoplasmic reticulum (ER) and likely support Ca(2+) release from intracellular stores by mediating cationic flux to maintain electrical neutrality. Deletion and point mutations in TRIC-B occur in families with autosomal recessive osteogenesis imperfecta. Tric-b knockout mice develop neonatal respiratory failure and exhibit poor bone ossification. We investigated the cellular defect causing the bone phenotype. Bone histology indicated collagen matrix deposition was reduced in Tric-b knockout mice. Osteoblasts, the bone-depositing cells, from Tric-b knockout mice exhibited reduced Ca(2+) release from ER and increased ER Ca(2+) content, which was associated with ER swelling. These cells also had impaired collagen release without a decrease in collagen-encoding transcripts, consistent with a defect in trafficking of collagen through ER. In contrast, osteoclasts, the bone-degrading cells, from Tric-b knockout mice were similar to those from wild-type mice. Thus, TRIC-B function is essential to support the production and release of large amounts of collagen by osteoblasts, which is necessary for bone mineralization.

SummaryFibrodysplasia ossificans progressiva (FOP) is a rare and intractable disorder characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor gain-of-function mutations in ACVR1 (FOP-ACVR1), a type I receptor for bone morphogenetic proteins. Despite numerous studies, no drugs have been approved for FOP. Here, we developed a high-throughput screening (HTS) system focused on the constitutive activation of FOP-ACVR1 by utilizing a chondrogenic ATDC5 cell line that stably expresses FOP-ACVR1. After HTS of 5,000 small-molecule compounds, we identified two hit compounds that are effective at suppressing the enhanced chondrogenesis of FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and suppressed the heterotopic ossification (HO) of multiple model mice, including FOP-ACVR1 transgenic mice and HO model mice utilizing FOP-iPSCs. Furthermore, we revealed that one of the hit compounds is an mTOR signaling modulator that indirectly inhibits mTOR signaling. Our results demonstrate that these hit compounds could contribute to future drug repositioning and the mechanistic analysis of mTOR signaling.