Stem cell regulation and hierarchical organization of human skeletal progenitors remain largely unexplored. Here, we report the isolation of a self-renewing and multipotent human skeletal stem cell ...(hSSC) that generates progenitors of bone, cartilage, and stroma, but not fat. Self-renewing and multipotent hSSCs are present in fetal and adult bones and can also be derived from BMP2-treated human adipose stroma (B-HAS) and induced pluripotent stem cells (iPSCs). Gene expression analysis of individual hSSCs reveals overall similarity between hSSCs obtained from different sources and partially explains skewed differentiation toward cartilage in fetal and iPSC-derived hSSCs. hSSCs undergo local expansion in response to acute skeletal injury. In addition, hSSC-derived stroma can maintain human hematopoietic stem cells (hHSCs) in serum-free culture conditions. Finally, we combine gene expression and epigenetic data of mouse skeletal stem cells (mSSCs) and hSSCs to identify evolutionarily conserved and divergent pathways driving SSC-mediated skeletogenesis.
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•PDPN+CD146−CD73+CD164+ marks a self-renewing, multipotent human skeletal stem cell•hSSCs can be isolated from fetal, adult, BMP2-treated human adipose stroma, and iPSCs•hSSCs undergo local expansion in response to acute skeletal injury•Comparison of mouse and human SSCs reveals evolutionary differences in skeletogenesis
Identification of a human skeletal stem cell reveals conserved and species-specific pathways in skeletal development, and response to injury and will guide future regenerative approaches.
Natural underwater adhesives Stewart, Russell J; Ransom, Todd C; Hlady, Vladimir
Journal of polymer science. Part B, Polymer physics,
1 June 2011, Volume:
49, Issue:
11
Journal Article
Peer reviewed
Open access
The general topic of this review is protein-based underwater adhesives produced by aquatic organisms. The focus is on mechanisms of interfacial adhesion to native surfaces and controlled underwater ...solidification of natural water-borne adhesives. Four genera that exemplify the broad range of function, general mechanistic features, and unique adaptations are discussed in detail: blue mussels, acorn barnacles, sandcastle worms, and freshwater caddisfly larva. Aquatic surfaces in nature are charged and in equilibrium with their environment, populated by an electrical double layer of ions as well as adsorbed natural polyelectrolytes and microbial biofilms. Surface adsorption of underwater bioadhesives likely occurs by exchange of surface bound ligands by amino acid sidechains, driven primarily by relative affinities and effective concentrations of polymeric functional groups. Most aquatic organisms exploit modified amino acid sidechains, in particular phosphorylated serines and hydroxylated tyrosines (dopa), with high-surface affinity that form coordinative surface complexes. After delivery to the surfaces as a fluid, permanent natural adhesives solidify to bear sustained loads. Mussel plaques are assembled in a manner superficially reminiscent of in vitro layer-by-layer strategies, with sequentially delivered layers associated through Fe(dopa)₃ coordination bonds. The adhesives of sandcastle worms, caddisfly larva, and barnacles may be delivered in a form somewhat similar to in vitro complex coacervation. Marine adhesives are secreted, or excreted, into seawater that has a significantly higher pH and ionic strength than the internal environment. Empirical evidence suggests these environment triggers could provide minimalistic, fail-safe timing mechanisms to prevent premature solidification (insolubilization) of the glue within the secretory system, yet allow rapid solidification after secretion. Underwater bioadhesives are further strengthened by secondary covalent curing.
The mammalian skeleton performs a diverse range of vital functions, requiring mechanisms of regeneration that restore functional skeletal cell populations after injury. We hypothesized that the Wnt ...pathway specifies distinct functional subsets of skeletal cell types, and that lineage tracing of Wnt-responding cells (WRCs) using the Axin2 gene in mice identifies a population of long-lived skeletal cells on the periosteum of long bone. Ablation of these WRCs disrupts healing after injury, and three-dimensional finite element modeling of the regenerate delineates their essential role in functional bone regeneration. These progenitor cells in the periosteum are activated upon injury and give rise to both cartilage and bone. Indeed, our findings suggest that WRCs may serve as a therapeutic target in the setting of impaired skeletal regeneration.
We present a new method that allows direct measurements of the glass transition temperature T_{g} at pressures up to 4.55 GPa in the glass-forming liquid cumene (isopropylbenzene). This new method ...uses a diamond anvil cell and can measure T_{g} at pressures of 10 GPa or greater. Measuring T_{g} at the glass→liquid transition involves monitoring the disappearance of pressure gradients initially present in the glass, but also takes advantage of the large increase in the volume expansion coefficient α_{p} at T_{g} as the supercooled or superpressed liquid is entered. Accurate T_{g}(P) values in cumene allow us to show that density scaling holds along this isochronous line up to pressures much higher than any previous study, corresponding to a density increase of 29%. Our results for cumene over this huge compression range yield ρ^{γ}/T=C, where C is a constant and where γ=4.77±0.02 for this nonassociated glass-forming system. Finally, high-pressure cumene viscosity data from the literature taken at much lower pressures and at several different temperatures, corresponding to a large dynamic range of nearly 13 orders of magnitude, are shown to superimpose on a plot of η vs ρ^{γ}/T for the same value of γ.
An unsolved problem in the viscoelastic properties of entangled linear polymers is the viscosity–molecular weight relationship. Experiments indicate a power law, η0 ∝ M a , with a = 3.5 ± 0.2, ...whereas the theoretical prediction for “pure reptation” is an exponent equal to 3.0. This discrepancy is ascribed to dynamic modes that compete with reptation so that a cubic dependence on M is observed only at sufficiently high molecular weights. That is, almost all existing experimental data are for polymers with too few entanglements to exhibit η0 ∝ M 3. To address this issue, we carried out experiments on polyisobutylene having as many as 430 entanglements per chain. Because reentanglement of polymer melts prepared from solution takes extraordinarily long times (another unsolved problem in rheology), annealing was carried out for 5 years prior to the viscosity measurements. We determined that at all temperatures, η0 was less than the extrapolation assuming the M 3.5 dependence of lower molecular weight polyisobutylene. This result is consistent with the idea that only at sufficiently high degrees of entanglement is pure reptation the operative mechanism, whereby linear flexible-chain polymers exhibit the predicted behavior. Our work is in good agreement with an earlier study on polybutadiene Colby, R. H.; Fetters, L. J.; Graessley, W. W. Melt viscosity-molecular weight relationship for linear polymers. Macromolecules 1987, 20, 2226–2237..
Regenerative paradigms exhibit nerve dependency, including regeneration of the mouse digit tip and salamander limb. Denervation impairs regeneration and produces morphological aberrancy in these ...contexts, but the direct effect of innervation on the stem and progenitor cells enacting these processes is unknown. We devised a model to examine nerve dependency of the mouse skeletal stem cell (mSSC), the progenitor responsible for skeletal development and repair. We show that after inferior alveolar denervation, mandibular bone repair is compromised because of functional defects in mSSCs. We present mSSC reliance on paracrine factors secreted by Schwann cells as the underlying mechanism, with partial rescue of the denervated phenotype by Schwann cell transplantation and by Schwann-derived growth factors. This work sheds light on the nerve dependency of mSSCs and has implications for clinical treatment of mandibular defects.
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•Denervation of the mandible impedes bone healing by impairing skeletal stem cells•Bone healing requires Schwann cell paracrine factors for proper stem cell function•Schwann cells and their signaling products rescue denervated mandibular healing
Jones et al. demonstrate the nerve dependency of mandibular bone repair after degeneration of the inferior alveolar nerve. Schwann cell paracrine signaling is required for skeletal stem cell enactment of bone healing. Rescue of healing by Schwann cell transplantation highlights skeletal stem cell-Schwann cell circuitry during mandibular repair.
Despite the peripheral nervous systems (PNS) capacity to regenerate, functional restoration is highly variable following peripheral nerve injury (PNI), oftentimes leading to persistent functional ...deficits. In the preclinical arena, advances in the therapeutic use of exogenous neurotrophic factors and synthetic neural scaffold technology hold promise in augmenting endogenous PNS regeneration following PNI. Clinical trials utilizing neurotrophic factors for other indications (eg, peripheral neuropathy) may provide insight into their role in PNI. Here we provide an updated review of progress made toward enhancing regeneration after PNI with a focus on neurotrophic factors and bioengineered scaffolds.
Cranial sutures are major growth centers for the calvarial vault, and their premature fusion leads to a pathologic condition called craniosynostosis. This study investigates whether skeletal ...stem/progenitor cells are resident in the cranial sutures. Prospective isolation by FACS identifies this population with a significant difference in spatio-temporal representation between fusing versus patent sutures. Transcriptomic analysis highlights a distinct signature in cells derived from the physiological closing PF suture, and scRNA sequencing identifies transcriptional heterogeneity among sutures. Wnt-signaling activation increases skeletal stem/progenitor cells in sutures, whereas its inhibition decreases. Crossing Axin2
mouse, endowing enhanced Wnt activation, to a Twist1
mouse model of coronal craniosynostosis enriches skeletal stem/progenitor cells in sutures restoring patency. Co-transplantation of these cells with Wnt3a prevents resynostosis following suturectomy in Twist1
mice. Our study reveals that decrease and/or imbalance of skeletal stem/progenitor cells representation within sutures may underlie craniosynostosis. These findings have translational implications toward therapeutic approaches for craniosynostosis.
The stroma in solid tumors contains a variety of cellular phenotypes and signaling pathways associated with wound healing, leading to the concept that a tumor behaves as a wound that does not heal. ...Similarities between tumors and healing wounds include fibroblast recruitment and activation, extracellular matrix (ECM) component deposition, infiltration of immune cells, neovascularization, and cellular lineage plasticity. However, unlike a wound that heals, the edges of a tumor are constantly expanding. Cell migration occurs both inward and outward as the tumor proliferates and invades adjacent tissues, often disregarding organ boundaries. The focus of our review is cancer associated fibroblast (CAF) cellular heterogeneity and plasticity and the acellular matrix components that accompany these cells. We explore how similarities and differences between healing wounds and tumor stroma continue to evolve as research progresses, shedding light on possible therapeutic targets that can result in innovative stromal-based treatments for cancer.
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