Abstract Orthopedic conditions have emerged as global health concerns, impacting approximately 1.7 billion individuals worldwide. However, the limited understanding of the underlying pathological processes at the cellular and molecular level has hindered the development of comprehensive treatment options for these disorders. The advent of single-cell RNA sequencing (scRNA-seq) technology has revolutionized biomedical research by enabling detailed examination of cellular and molecular diversity. Nevertheless, investigating mechanisms at the single-cell level in highly mineralized skeletal tissue poses technical challenges. In this comprehensive review, we present a streamlined approach to obtaining high-quality single cells from skeletal tissue and provide an overview of existing scRNA-seq technologies employed in skeletal studies along with practical bioinformatic analysis pipelines. By utilizing these methodologies, crucial insights into the developmental dynamics, maintenance of homeostasis, and pathological processes involved in spine, joint, bone, muscle, and tendon disorders have been uncovered. Specifically focusing on the joint diseases of degenerative disc disease, osteoarthritis, and rheumatoid arthritis using scRNA-seq has provided novel insights and a more nuanced comprehension. These findings have paved the way for discovering novel therapeutic targets that offer potential benefits to patients suffering from diverse skeletal disorders. 

pdf/advancing-skeletal-health-and-disease-research-with-single-1ztxsrxwou.pdf

Advancing skeletal health and disease research with single-cell RNA sequencing

Direct cell‐fate conversion by chemical reprogramming is promising for regenerative cell therapies. However, this process requires the reactivation of a set of master transcription factors (TFs) of the target cell type, which has proven challenging using only small molecules.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/jcsm.13155

Chemical reprogramming of melanocytes to skeletal muscle cells

Abstract Skeletal muscle represents a highly organized tissue that primarily regenerates by myogenic stem cells. Mimicking an in vitro skeletal muscle differentiation program that contains self‐renewing muscle stem cells and aligned myotubes is considered challenging. This study presents the engineering of a biomimetic muscle construct that can self‐regenerate and produce aligned myotubes using induced myogenic progenitor cells (iMPCs), a heterogeneous culture consisting of skeletal muscle stem, progenitor, and differentiated cells. Utilizing electrospinning, polycaprolactone (PCL) substrates are fabricated to facilitate iMPC‐differentiation into aligned myotubes by controlling PCL fiber orientation. Newly‐conceived constructs contain organized multinucleated myotubes alongside self‐renewing stem cells, whose differentiation capacity is augmented by Matrigel supplementation. Furthermore, this work utilizes single‐cell RNA‐sequencing (scRNA‐seq) to demonstrate that iMPC‐derived constructs faithfully recapitulate a step‐wise myogenic differentiation program. Notably, when subjected to a damaging myonecrotic agent, self‐renewing stem cells rapidly differentiate into aligned myotubes within the constructs, akin to skeletal muscle repair in vivo. Finally, this study demonstrates that the iMPC derivation protocol can be adapted to engineer human myoblast‐derived muscle constructs containing aligned myotubes, showcasing potential for translational applicability. Taken together, this work reports a novel in vitro system that mirrors myogenic regeneration and skeletal muscle alignment for basic research and regenerative medicine. 

A Self‐Renewing Biomimetic Skeletal Muscle Construct Engineered using Induced Myogenic Progenitor Cells

Getting mature and functional stem cell-derived, insulin-producing β cells is an important step for disease modeling, drug screening, and cell replacement therapy. In this issue, Hua et al. 1 Hua H. Wang Y. Wang X. Wang S. Zhou Y. Liu Y. Liang Z. Ren H. Lu S. Wu S. et al. Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived β cells. Cell Stem Cell. 2024; 31: 850-865.e10https://doi.org/10.1016/j.stem.2024.04.010 Abstract Full Text Full Text PDF Scopus (0) Google Scholar used single-cell multiomics analysis coupled with chemical screening to identify a crucial role for ceramides in generating mature stem cell-derived β cells. Getting mature and functional stem cell-derived, insulin-producing β cells is an important step for disease modeling, drug screening, and cell replacement therapy. In this issue, Hua et al. 1 Hua H. Wang Y. Wang X. Wang S. Zhou Y. Liu Y. Liang Z. Ren H. Lu S. Wu S. et al. Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived β cells. Cell Stem Cell. 2024; 31: 850-865.e10https://doi.org/10.1016/j.stem.2024.04.010 Abstract Full Text Full Text PDF Scopus (0) Google Scholar used single-cell multiomics analysis coupled with chemical screening to identify a crucial role for ceramides in generating mature stem cell-derived β cells. Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived β cellsHua et al.Cell Stem CellMay 1, 2024In BriefHua et al. conducted single-cell multi-omics analysis during hPSC-islet maturation post transplantation. They discovered that ceramide homeostasis was remodeled during β cell maturation. Through targeting the maturation dominators, they identified the small molecule TH34 as significantly enhancing the maturation of hPSC-β cells in vitro by reducing intracellular ceramides. Full-Text PDF 

Greasing the machinery toward maturation of stem cell-derived β cells

Generating functional β cells from stem cells remains a major challenge in regenerative medicine due to the incomplete recapitulation of human pancreatic development in vitro. By integrating newly generated human single-cell RNA sequencing (RNA-seq) datasets (Carnegie stages 10-15) with existing data, we mapped gene co-expression networks (GCNs) underlying pancreatic lineage progression in humans and mice. We observed significant species-specific differences in GCN robustness and dorsal-ventral propensity for progenitor development. Benchmarking three common differentiation protocols against the in vivo datasets showed that they fail to reproduce human-like GCNs, thereby limiting stem cell-derived insulin-secreting β cell (SC-β cell) induction efficiency. To address this, we developed a protocol that reconstructs human pancreatic GCN dynamics, shortens the induction period to 19 days, and achieves up to ∼70% β cell content. SC-islets generated with this method significantly alleviated diabetic symptoms and maintained mature β cell function after transplantation in mice. These findings bridge in vivo mechanisms and in vitro differentiation, advancing stem cell-based therapies.

Reconstructing human pancreatic gene networks enhances stem cell-derived β cell induction

Human pluripotent stem cell-derived β cells (hPSC-β cells) show the potential to restore euglycemia. However, the immature functionality of hPSC-β cells has limited their efficacy in application. Here, by deciphering the continuous maturation process of hPSC-β cells post transplantation via single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), we show that functional maturation of hPSC-β cells is an orderly multistep process during which cells sequentially undergo metabolic adaption, removal of negative regulators of cell function, and establishment of a more specialized transcriptome and epigenome. Importantly, remodeling lipid metabolism, especially downregulating the metabolic activity of ceramides, the central hub of sphingolipid metabolism, is critical for β cell maturation. Limiting intracellular accumulation of ceramides in hPSC-β cells remarkably enhanced their function, as indicated by improvements in insulin processing and glucose-stimulated insulin secretion. In summary, our findings provide insights into the maturation of human pancreatic β cells and highlight the importance of ceramide homeostasis in function acquisition. 

Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived β cells.

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Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived β cells.

Chemical reprogramming of melanocytes to skeletal muscle cells