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Osteoimmunology peeks into the interaction of bone and the immune system, which has largely proved to be a multiplex reaction. Osteocytes have been shown to regulate bone resorption through the expression of RANKL in physiologic and pathologic conditions. TNF-α, a product of the immune system, is an important cytokine regulating bone resorption in inflammatory conditions either directly or by increasing RANKL and M-CSF expressions by osteoblasts and stromal cells. The effect of TNF-α on a wide range of cell types has been documented; however, the direct effect of TNF-α on osteocytes has not been established yet. In this study, primary osteocytes were isolated by cell sorting from neonatal calvaria of Dmp1-Topaz mice, which express the green fluorescent protein under the influence of dentin matrix protein 1 promoter. The results show that osteocytes have a significantly higher RANKL mRNA expression when cultured with TNF-α. A co-culture system of osteocytes and TNF receptors I and II deficient osteoclast precursors treated with TNF-α show a significant increase in TRAP-positive cells while cultures without TNF-α failed to show TRAP-positive cells. Additionally, experiments of TNF-α injected to mouse calvaria show an increase in TRAP-positive cell number in the suture mesenchyme and an increase in the percentage of RANKL-positive osteocytes compared to PBS-injected calvaria. Osteocytes cultured with TNF-α show up-regulation of MAPKs phosphorylation measured by western blot, and adding MAPKs inhibitors to osteocytes cultured with TNF-α significantly decreases RANKL mRNA expression compared to osteocytes cultured with TNF-α alone. We also found that TNF-α activates the NF-κB pathway in osteocytes measured as a function of p65 subunit nuclear translocation. TNF-α directly affects osteocyte RANKL expression and increases osteoclastogenesis; our results demonstrate that osteocytes guard an important role in inflammatory bone resorption mediated by TNF-α.

Fossil hominins from South Africa are enriching the story of early human evolution and dispersal. Herries et al. describe the geological context and dating of the hominin-bearing infilled cave, or palaeocave, at a site called Drimolen in South Africa (see the Perspective by Antón). They focus on the age and context of a recently discovered Homo erectus sensu lato fossil and a Paranthropus robustus fossil, which they dated to ∼2.04 million to 1.95 million years ago. This makes Drimolen one of the best-dated sites in South Africa and establishes these fossils as the oldest definitive specimens of their respective species ever discovered. The age confirms that species of Australopithecus, Paranthropus , and early Homo overlapped in the karst of South Africa ∼2 million years ago. Science , this issue p. eaaw7293 ; see also p. 34 Multiple hominin genera, including the earliest Homo erectus lineage, were present in South Africa 2 million years ago. Understanding the extinction of Australopithecus and origins of Paranthropus and Homo in South Africa has been hampered by the perceived complex geological context of hominin fossils, poor chronological resolution, and a lack of well-preserved early Homo specimens. We describe, date, and contextualize the discovery of two hominin crania from Drimolen Main Quarry in South Africa. At ~2.04 million to 1.95 million years old, DNH 152 represents the earliest definitive occurrence of Paranthropus robustus , and DNH 134 represents the earliest occurrence of a cranium with clear affinities to Homo erectus . These crania also show that Homo , Paranthropus , and Australopithecus were contemporaneous at ~2 million years ago. This high taxonomic diversity is also reflected in non-hominin species and provides evidence of endemic evolution and dispersal during a period of climatic variability.

Bioprinting has emerged as a novel technological approach with the potential to address unsolved questions in the field of tissue engineering. We have recently shown that Laser Assisted Bioprinting (LAB), due to its unprecedented cell printing resolution and precision, is an attractive tool for the in situ printing of a bone substitute. Here, we show that LAB can be used for the in situ printing of mesenchymal stromal cells, associated with collagen and nano-hydroxyapatite, in order to favor bone regeneration, in a calvaria defect model in mice. Also, by testing different cell printing geometries, we show that different cellular arrangements impact on bone tissue regeneration. This work opens new avenues on the development of novel strategies, using in situ bioprinting, for the building of tissues, from the ground up.

Bone graft granules are valuable tools for ridge area bone grafting owing to their ease of manipulation and interconnected porous structure. Guided bone regeneration (GBR) using barrier membranes is commonly used for alveolar ridge augmentation; however, the surgical procedures are technically complicated. In this study, we fabricated bioresorbable mesh domes (BMDs) using two types of Vicryl mesh (woven and knitted types) containing carbonate apatite granules. BMD samples were prepared in three groups: upper sides made from the woven type (UW) and lower sides made from the woven type (LW) (the UW/LW group), upper sides made from the woven type (UW) and lower sides made from the knitted type (LK) (the UW/LK group), and upper sides made from the knitted type (UK) and lower sides made from the knitted type (LK) (the UK/LK group). The samples were subsequently implanted into rabbit calvaria, and radiomorphometric and histological analyses were conducted. The UK/LK group exhibited enhanced appositional bone formation because the knitted mesh on the skin side prevented the infiltration of a substantial amount of fibrous tissue. This increase in bone formation could be attributed to the interaction between granules and osteoprogenitors that pass through the mesh from the host bone. Conversely, the UW/LW and UW/LK groups presented limited appositional bone formation. Compared with knitted mesh, woven mesh might tend to be absorbed over a short span, allowing fibrous tissue invasion and inhibiting new bone formation. Additionally, BMDs could retain granules in a targeted location and avoid displacement of the granules to unintended locations. Graphical Abstract

Growth factors in serum-free conditioned media from human bone marrow-derived mesenchymal stem cells (MSC-CM) are known to be effective in bone regeneration. However, the secretomes in MSC-CM that act as active ingredients for bone regeneration, as well as their mechanisms, remains unclear. Exosomes, components of MSC-CM, provide the recipient cells with genetic information and enhance the recipient cellular paracrine stimulation, which contributes to tissue regeneration. We hypothesized that MSC-CM-derived exosomes (MSC-Exo) promoted bone regeneration, and that angiogenesis was a key step. Here, we prepared an MSC-Exo group, MSC-CM group, and Exo-antiVEGF group (MSC-Exo with angiogenesis inhibitor), and examined the osteogenic and angiogenic potential in MSCs. Furthermore, we used a rat model of calvaria bone defect and implanted each sample to evaluate bone formation weekly, until week 4 after treatment. Results showed that MSC-Exo enhanced cellular migration and osteogenic and angiogenic gene expression in MSCs compared to that in other groups. In vivo, early bone formation by MSC-Exo was also confirmed. Two weeks after implantation, the newly formed bone area was 31.5 ± 6.5% in the MSC-Exo group while those in the control and Exo-antiVEGF groups were 15.4 ± 4.4% and 8.7 ± 1.1%, respectively. Four weeks after implantation, differences in the area between the MSC-Exo group and the Exo-antiVEGF or control groups were further broadened. Histologically, notable accumulation of osteoblast-like cells and vascular endothelial cells was observed in the MSC-Exo group; however, fewer cells were found in the Exo-antiVEGF and control groups. In conclusion, MSC-Exo promoted bone regeneration during early stages, as well as enhanced angiogenesis. Considering the tissue regeneration with transplanted cells and their secretomes, this study suggests that exosomes might play an important role, especially in angiogenesis.

The existence of specialised structures that allow a continuous exchange of CSF between different anatomical compartments at the brain–meningeal border is challenging conventional notions around molecular transport within the brain. Experimental findings highlight the conduits and cellular structures controlling the transport of CSF and immune cells between the brain parenchyma (via the glymphatic system), the subarachnoid space (enclosed by the meningeal pia and arachnoid layers), and the outmost meningeal dural layer and calvaria (via the so-called arachnoid cuff exit points). Studies in both rodent models and humans show new mechanisms of brain glymphatic molecular transport, meningeal lymphatic vascular drainage, and immune surveillance at the brain-draining skull bone marrow and cervical lymph nodes. Pathological alterations at the brain–meningeal border have been implicated in disorders of diverse causes, from traumatic brain injury to Alzheimer's disease.

Human skeletal stem cells (SSCs) have been discovered in fetal and adult long bones. However, the spatiotemporal ontogeny of human embryonic SSCs during early skeletogenesis remains elusive. Here we map the transcriptional landscape of human limb buds and embryonic long bones at single-cell resolution to address this fundamental question. We found remarkable heterogeneity within human limb bud mesenchyme and epithelium, and aligned them along the proximal–distal and anterior–posterior axes using known marker genes. Osteo-chondrogenic progenitors first appeared in the core limb bud mesenchyme, which give rise to multiple populations of stem/progenitor cells in embryonic long bones undergoing endochondral ossification. Importantly, a perichondrial embryonic skeletal stem/progenitor cell (eSSPC) subset was identified, which could self-renew and generate the osteochondral lineage cells, but not adipocytes or hematopoietic stroma. eSSPCs are marked by the adhesion molecule CADM1 and highly enriched with FOXP1/2 transcriptional network. Interestingly, neural crest-derived cells with similar phenotypic markers and transcriptional networks were also found in the sagittal suture of human embryonic calvaria. Taken together, this study revealed the cellular heterogeneity and lineage hierarchy during human embryonic skeletogenesis, and identified distinct skeletal stem/progenitor cells that orchestrate endochondral and intramembranous ossification.

H omo erectus is the founding early hominin species of Island Southeast Asia, and reached Java (Indonesia) more than 1.5 million years ago 1 , 2 . Twelve H. erectus calvaria (skull caps) and two tibiae (lower leg bones) were discovered from a bone bed located about 20 m above the Solo River at Ngandong (Central Java) between 1931 and 1933 3 , 4 , and are of the youngest, most-advanced form of H. erectus 5 – 8 . Despite the importance of the Ngandong fossils, the relationship between the fossils, terrace fill and ages have been heavily debated 9 – 14 . Here, to resolve the age of the Ngandong evidence, we use Bayesian modelling of 52 radiometric age estimates to establish—to our knowledge—the first robust chronology at regional, valley and local scales. We used uranium-series dating of speleothems to constrain regional landscape evolution; luminescence, 40 argon/ 39 argon ( 40 Ar/ 39 Ar) and uranium-series dating to constrain the sequence of terrace evolution; and applied uranium-series and uranium series–electron-spin resonance (US–ESR) dating to non-human fossils to directly date our re-excavation of Ngandong 5 , 15 . We show that at least by 500 thousand years ago (ka) the Solo River was diverted into the Kendeng Hills, and that it formed the Solo terrace sequence between 316 and 31 ka and the Ngandong terrace between about 140 and 92 ka. Non-human fossils recovered during the re-excavation of Ngandong date to between 109 and 106 ka (uranium-series minimum) 16 and 134 and 118 ka (US–ESR), with modelled ages of 117 to 108 thousand years (kyr) for the H. erectus bone bed, which accumulated during flood conditions 3 , 17 . These results negate the extreme ages that have been proposed for the site and solidify Ngandong as the last known occurrence of this long-lived species. Bayesian modelling of radiometric age estimates provides a robust chronology for Homo erectus at Ngandong (Java), confirming that this site currently represents the last known occurrence of this species.

Highly accurate detection of intracranial hemorrhages (ICH) on head computed tomography (HCT) scans can prove challenging at high-volume centers. This study aimed to determine the number of additional ICHs detected by an artificial intelligence (AI) algorithm and to evaluate reasons for erroneous results at a level I trauma center with teleradiology services. In a retrospective multi-center cohort study, consecutive emergency non-contrast HCT scans were analyzed by a commercially available ICH detection software (AIDOC, Tel Aviv, Israel). Discrepancies between AI analysis and initial radiology report (RR) were reviewed by a blinded neuroradiologist to determine the number of additional ICHs detected and evaluate reasons leading to errors. 4946 HCT (05/2020-09/2020) from 18 hospitals were included in the analysis. 205 reports (4.1%) were classified as hemorrhages by both radiology report and AI. Out of a total of 162 (3.3%) discrepant reports, 62 were confirmed as hemorrhages by the reference neuroradiologist. 33 ICHs were identified exclusively via RRs. The AI algorithm detected an additional 29 instances of ICH, missed 12.4% of ICH and overcalled 1.9%; RRs missed 10.9% of ICHs and overcalled 0.2%. Many of the ICHs missed by the AI algorithm were located in the subarachnoid space (42.4%) and under the calvaria (48.5%). 85% of ICHs missed by RRs occurred outside of regular working-hours. Calcifications (39.3%), beam-hardening artifacts (18%), tumors (15.7%), and blood vessels (7.9%) were the most common reasons for AI overcalls. ICH size, image quality, and primary examiner experience were not found to be significantly associated with likelihood of incorrect AI results. Complementing human expertise with AI resulted in a 12.2% increase in ICH detection. The AI algorithm overcalled 1.9% HCT. German Clinical Trials Register (DRKS-ID: DRKS00023593).

Chemical modification of gelatin using epigallocatechin gallate (EGCG) promotes bone formation in vivo. However, further improvements are required to increase the mechanical strength and bone-forming ability of fabricated EGCG-modified gelatin sponges (EGCG-GS) for practical applications in regenerative therapy. In the present study, we investigated whether vacuum heating-induced dehydrothermal cross-linking of EGCG-GS enhances bone formation in critical-sized rat calvarial defects. The bone-forming ability of vacuum-heated EGCG-GS (vhEGCG-GS) and other sponges was evaluated by micro-computed tomography and histological staining. The degradation of sponges was assessed using protein assays, and cell morphology and proliferation were verified by scanning electron microscopy and immunostaining using osteoblastic UMR106 cells in vitro. Four weeks after the implantation of sponges, greater bone formation was detected for vhEGCG-GS than for EGCG-GS or vacuum-heated gelatin sponges (dehydrothermal cross-linked sponges without EGCG). In vitro experiments revealed that the relatively low degradability of vhEGCG-GS supports cell attachment, proliferation, and cell–cell communication on the matrix. These findings suggest that vacuum heating enhanced the bone forming ability of EGCG-GS, possibly via the dehydrothermal cross-linking of EGCG-GS, which provides a scaffold for cells, and by maintaining the pharmacological effect of EGCG.