Biology subjects

Koyama, E.

Publications and source records attributed to Koyama, E..

5 recordsLinked to original sources

bioRxiv2026

Impaired loading following denervation elicits dynamic, differential growth trajectories of musculoskeletal tissues

Physical forces dictate the function and maintenance of adult musculoskeletal tissues. Yet, the impact of biophysical cues on the growth and maturation of these tissues, especially dense connective tissues, remains unclear. Here, we investigated the effects of neonatal mechanical loading on early postnatal growth of the musculoskeletal tissues of the lower limb, with particular focus on the Achilles tendon. We performed sciatic nerve resection (SNR) on one-day-old mice to denervate the hamstrings and distal hindlimb muscles. Sciatic Nerve Resection resulted in severe and sustained alterations in gait, accompanied by an altered transcriptional landscape in distal musculoskeletal tissues, with marked reductions in bone and tendon growth and smaller, fibrotic hindlimb musculature. Sciatic nerve resection impaired cumulative growth in the Achilles tendon, shifting cell proliferation and matrix-driven growth trajectories and altering mechanotransduction gene programs toward inflammation and matrix catabolism with age. This work highlights the essential role of mechanical loading in driving mechanosignaling and postnatal growth trajectories in musculoskeletal tissues of the developing limb, with implications for overall musculoskeletal health in adulthood.

bioengineering↗

bioRxiv2025

A pivotal role for Wnt antagonists in constraining Wnt activity to promote digit joint specification.

Bmps and Wnts play opposing roles in several contexts during chondrogenesis and joint formation. Using genetic and genomic approaches, we found instead that canonical Wnts can cooperate with Bmps to enhance pSmad1/5 activity and initiate chondrogenic commitment in digit tip progenitors. 5Hoxd{Delta}/{Delta} mutant digits are characterized by elevated Bmp and pSmad1/5 activity and subsequent joint loss. We show that expressing stabilized {beta}catenin ({beta}catCA) in interdigit mesenchyme rescues 5Hoxd{Delta}/{Delta} digit joint loss non-autonomously, by inducing secreted Wnt antagonists and normalizing digit tip pSmad1/5 levels. Indeed, genetic removal of Dkk2 in 5Hoxd{Delta}/{Delta} prevented joint rescue by {beta}catCA. Furthermore, elevating Wnt activity with Gsk3{beta} antagonists in limb bud culture stabilized pSmad1/5 levels and enhanced Bmp activity. Elevated pSmad1/5, as seen in 5Hoxd{Delta}/{Delta}, accelerates chondrogenic commitment, impeding a switch of phalanx forming region (PFR) cells in the digit tip to interzone (joint progenitor) fate. We propose that, before progenitors transit into PFR, Wnt antagonists cooperate with Fgfs to prevent precocious pSmad1/5 accumulation by stabilizing Gsk3{beta} to promote Smad-linker phosphorylation and Smad1/5 degradation. Consequently, Wnt antagonists play a key role in modulating the pace of initial commitment of digit progenitors to chondrogenesis, together with Fgfs, and maintain mesenchymal plasticity to balance digit phalanx and joint formation.

developmental biology↗

bioRxiv2021

Primary cilia drive postnatal tidemark patterning in articular cartilage by coordinating responses to Indian Hedgehog and mechanical load

Articular cartilage (AC) is essential for body movement, but is highly susceptible to degenerative diseases and has poor self-repair capacity. To improve current subpar regenerative treatment, developmental mechanisms of AC should be clarified and, specifically, how postnatal multi-zone organization is acquired. Primary cilia are cell surface organelles crucial for mammalian tissue morphogenesis and while the importance of chondrocyte primary cilia is well appreciated their specific roles in postnatal AC morphogenesis remain unclear. To explore these mechanisms, we used a murine conditional loss-of-function approach (Ift88-flox) targeting joint-lineage progenitors (Gdf5Cre) and monitored postnatal knee AC development. Joint formation and growth up to juvenile stages were largely unaffected, however mature AC (aged 2 months) exhibited disorganized extracellular matrix, decreased aggrecan and collagen II due to reduced gene expression (not increased catabolism), and marked reduction of AC modulus by 30-50%. In addition, we discovered the surprising findings that tidemark patterning was severely disrupted and accompanied alterations in hedgehog signaling that were also dependent on regional load-bearing functions of AC. Interestingly, Prg4 expression was also increased in those loaded sites. Together, our data provide evidence that primary cilia orchestrate postnatal AC morphogenesis, dictating tidemark topography, zonal matrix composition and mechanical load responses.

developmental biology↗

bioRxiv2021

Intrinsic and growth-mediated cell and matrix specialization during meniscus tissue assembly

The incredible mechanical strength and durability of mature fibrous tissues and their extremely limited turnover and regenerative capacity underscores the importance of proper matrix assembly during early postnatal growth. In tissues with composite extracellular matrix (ECM) structures, such as the adult knee meniscus, fibrous (Collagen-I rich) and cartilaginous (Collagen-II, proteoglycan-rich) matrix components are regionally segregated to the outer and inner portions of the tissue. While this spatial variation in composition is appreciated to be functionally important for resisting complex mechanical loads associated with gait, the establishment of these specialized zones is poorly understood. To address this issue, the following study tracked the growth of the murine meniscus from its embryonic formation through its first month of growth, encompassing the critical time-window during which animals begin to ambulate and weight bear. Using histological analysis, region specific high-throughput qPCR, and Col-1 and Col-2 fluorescent reporter mice, we found that matrix and cellular features defining specific tissue zones were already present at birth, before continuous weight-bearing had occurred. These differences were further refined with postnatal growth and maturation, resulting in specialization of mature tissue regions. Taken together, this work establishes a detailed timeline of the concurrent spatiotemporal changes that occur at both the cellular and matrix level throughout meniscus maturation. The findings of this study provide a framework for investigating the reciprocal feedback between cells and their evolving microenvironments during assembly of a mechanically robust fibrocartilage tissue, thus providing insight into mechanisms of tissue degeneration and effective regenerative strategies.

developmental biology↗

bioRxiv2020

Identification of Gli1 as a progenitor cell marker for meniscus development and injury repair

Meniscal tears are associated with a high risk of osteoarthritis but currently have no disease-modifying therapies. Using Gli1-CreER tdTomato mice, we found that Gli1+ cells contribute to the development of meniscus horns from 2 weeks of age. In adult mice, Gli1+ cells resided at the superficial layer of meniscus and expressed known mesenchymal progenitor markers. In culture, meniscal Gli1+ cells possessed high progenitor activities under the control of Hh signal. Meniscus injury at the anterior horn induced a quick expansion of Gli1+ cells. Normally, the tissue healed slowly, leading to cartilage degeneration. Ablation of Gli1+ cells further hindered this repair process. Strikingly, intra-articular injection of Gli1+ meniscal cells or an Hh activator right after injury accelerated the bridging of the interrupted ends and attenuated signs of osteoarthritis. Taken together, our work identified a novel progenitor population in meniscus and proposes a new treatment for repairing injured meniscus and preventing osteoarthritis.

developmental biology↗