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The ultimate goal of this study is to regenerate lost dental pulp and dentin via stem/progenitor cell–based approaches and tissue engineering technologies. In this study, we tested the possibility of regenerating vascularized human dental pulp in emptied root canal space and producing new dentin on existing dentinal walls using a stem/progenitor cell–mediated approach with a human root fragment and an immunocompromised mouse model. Stem/progenitor cells from apical papilla and dental pulp stem cells were isolated, characterized, seeded onto synthetic scaffolds consisting of poly-D,L-lactide/glycolide, inserted into the tooth fragments, and transplanted into mice. Our results showed that the root canal space was filled entirely by a pulp-like tissue with well-established vascularity. In addition, a continuous layer of dentin-like tissue was deposited onto the canal dentinal wall. This dentin-like structure appeared to be produced by a layer of newly formed odontoblast-like cells expressing dentin sialophosphoprotein, bone sialoprotein, alkaline phosphatase, and CD105. The cells in regenerated pulp-like tissue reacted positively to anti-human mitochondria antibodies, indicating their human origin. This study provides the first evidence showing that pulp-like tissue can be regenerated de novo in emptied root canal space by stem cells from apical papilla and dental pulp stem cells that give rise to odontoblast-like cells producing dentin-like tissue on existing dentinal walls.

Objectives To assess the safety and therapeutic effects of allogeneic human dental pulp stem cells (DPSCs) in treating severe pneumonia caused by COVID-19. Trial design This is a single centre, two arm ratio 1:1, triple blinded, randomized, placebo-controlled, parallel group, clinical trial. Participants Twenty serious COVID-19 cases will be enrolled in the trial from April 6th to December 31st 2020. Inclusion Criteria: hospitalised patients at Renmin Hospital of Wuhan University satisfy all criteria as below: Adults aged 18-65 years; Voluntarily participate in this clinical trial and sign the “informed consent form” or have consent from a legal representative. Diagnosed with severe pneumonia of COVID-19: nucleic acid test SARS-CoV-2 positive; respiratory distress (respiratory rate > 30 times / min); hypoxia (resting oxygen saturation < 93% or arterial partial pressure of oxygen / oxygen concentration < 300 mmHg). COVID-19 featured lung lesions in chest X-ray image. Exclusion Criteria: Patients will be excluded from the study if they meet any of the following criteria. Patients have received other experimental treatment for COVID-19 within the last 30 days; Patients have severe liver condition (e.g., Child Pugh score >=C or AST> 5 times of the upper limit); Patients with severe renal insufficiency (estimated glomerular filtration rate <=30mL / min/1.73 m 2 ) or patients receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis; Patients who are co-infected with HIV, hepatitis B, tuberculosis, influenza virus, adenovirus or other respiratory infection viruses; Female patients who have no sexual protection in the last 30 days prior to the screening assessment; Pregnant or lactating women or women using estrogen contraception; Patients who are planning to become pregnant during the study period or within 6 months after the end of the study period; Other conditions that the researchers consider not suitable for participating in this clinical trial. Intervention and comparator There will be two study groups: experimental and control. Both will receive all necessary routine treatment for COVID-19. The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x10 7 human DPSCs in 30ml saline solution) on day 1, 4 and 7; The control group will receive an equal amount of saline (placebo) on the same days. Clinical and laboratory observations will be performed for analysis during a period of 28 days for each case since the commencement of the study. Main outcomes 1. Primary outcome The primary outcome is Time To Clinical Improvement (TTCI). By definition, TTCI is the time (days) it takes to downgrade two levels from the following six ordered grades [(grade 1) discharge to (grade 6) death] in the clinical state of admission to the start of study treatments (hDPSCs or placebo). Six grades of ordered variables: Grade Description Grade 1: Discharged of patient; Grade 2: Hospitalized without oxygen supplement; Grade 3: Hospitalized, oxygen supplement is required, but NIV / HFNC is not required; Grade 4: Hospitalized in intensive care unit, and NIV / HFNC treatment is required; Grade 5: Hospitalized in intensive care unit, requiring ECMO and/or IMV; Grade 6: Death. Abbreviations: NIV, non-invasive mechanical ventilation; HFNC, high-flow nasal catheter; IMV, invasive mechanical ventilation. 2. Secondary outcomes 2.1 vital signs: heart rate, blood pressure (systolic blood pressure, diastolic blood pressure). During the screening period, hospitalization every day (additional time points of D1, D4, D7 30min before injection, 2h ± 30min, 24h ± 30min after the injection) and follow-up period D90 ± 3 days. 2.2 Laboratory examinations: during the screening period, 30 minutes before D1, D4, D7 infusion, 2h ± 30min, 24h ± 30min after the end of infusion, D10, D14, D28 during hospitalization or discharge day and follow-up period D90 ± 3 days. 2.3 Blood routine: white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils, lymphocytes, monocytes, eosinophils Acidic granulocyte count, basophil count, red blood cell, hemoglobin, hematocrit, average volume of red blood cells, average red blood cell Hb content, average red blood cell Hb concentration, RDW standard deviation, RDW coefficient of variation, platelet count, platelet specific platelet average Volume, platelet distribution width,% of large platelets; 2.4 Liver and kidney function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, prealbumin, total protein, albumin, globulin, white / globule ratio , Total bilirubin, direct bilirubin, cholinesterase, urea, creatinine, total carbon dioxide, uric acid glucose, potassium, sodium, chlorine, calcium, corrected calcium, magnesium, phosphorus, calcium and phosphorus product, anion gap, penetration Pressure, total cholesterol, triacylglycerol, high density lipoprotein cholesterol, Low density lipoprotein cholesterol, lipoprotein a, creatine kinase, lactate dehydrogenase, estimated glomerular filtration rate. 2.5 Inflammation indicators: hypersensitive C-reactive protein, serum amyloid (SAA); 2.6 Infectious disease testing: Hepatitis B (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb), Hepatitis C (Anti-HCV), AIDS (HIVcombin), syphilis (Anti-TP), cytomegalovirus CMV-IgM, cytomegalovirus CMV-IgG; only during the screening period and follow-up period D90 ± 3. 2.7 Immunological testing: Collect peripheral blood to detect the phenotype of T lymphocyte, B lymphocyte, natural killer cell, Macrophage and neutrophil by using flow cytometry. Collect peripheral blood to detect the gene profile of mononuclear cells by using single-cell analyses. Collect peripheral blood serum to detect various immunoglobulin changes: IgA, IgG, IgM, total IgE; Collect peripheral blood serum to explore the changes of cytokines, Th1 cytokines (IL-1 β, IL-2, TNF-a, ITN-γ), Th2 cytokines (IL-4, IL-6, IL -10). 2.8 Pregnancy test: blood β-HCG, female subjects before menopause are examined during the screening period and follow-up period D90 ± 3. 2.9 Urine routine: color, clarity, urine sugar, bilirubin, ketone bodies, specific gravity, pH, urobilinogen, nitrite, protein, occult blood, leukocyte enzymes, red blood cells, white blood cells, epithelial cells, non-squamous epithelial cells , Transparent cast, pathological cast, crystal, fungus; 2.10 Stool Routine: color, traits, white blood cells, red blood cells, fat globules, eggs of parasites, fungi, occult blood (chemical method), occult blood (immune method), transferrin (2h ± 30min after the injection and not detected after discharge). Randomization Block randomization method will be applied by computer to allocate the participants into experimental and control groups. The random ratio is 1:1. Blinding (masking) Participants, outcomes assessors and investigators (including personnel in laboratory and imaging department who issue the sample report or image observations) will be blinded. Injections of cell suspension and saline will be coded in accordance with the patient’s randomisation group. The blind strategy is kept by an investigator who does not deliver the medical care or assess primary outcome results. Numbers to be randomized (sample size) Twenty participants will be randomized to the experimental and control groups (10 per group). Trial Status Protocol version number, hDPSC-CoVID-2019-02-2020 Version 2.0, March 13, 2020. Patients screening commenced on 16 th April and an estimated date of the recruitment of the final participants will be around end of July. . Trial registration Registration: World Health Organization Trial Registry: ChiCTR2000031319; March 27,2020. ClinicalTrials.gov Identifier: NCT04336254; April 7, 2020 Other Study ID Numbers: hDPSC-CoVID-2019-02-2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

The dentin exposure always leads to dentin hypersensitivity and/or caries. Given the dentin's tubular structure and low mineralization degree, reestablishing an effective biobarrier to stably protect dentin remains significantly challenging. This study reports a versatile dentin surface biobarrier consisting of a mesoporous silica-based epigallocatechin-3-gallate (EGCG)/nanohydroxyapatite delivery system and evaluates its stability on the dentinal tubule occlusion and the ( ) biofilm inhibition. The mesoporous delivery system was fabricated and characterized. Sensitive dentin discs were prepared and randomly allocated to three groups: 1, control group; 2, casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) group; and 3, the mesoporous delivery system group. The dentin permeability, dentinal tubule occlusion, acid and abrasion resistance, and biofilm inhibition were determined for 1 week and 1 month. The in vitro release profiles of EGCG, Ca, and P were also monitored. The mesoporous delivery system held the ability to sustainably release EGCG, Ca, and P and could persistently occlude dentinal tubules with acid and abrasion resistance, reduce the dentin permeability, and inhibit the biofilm formation for up to 1 month compared with the two other groups. The system provided prolonged stability to combat oral adverse challenges and served as an effective surface biobarrier to protect the exposed dentin. The establishment of the dentin surface biobarrier consisting of a mesoporous delivery system indicates a promising strategy for the prevention and the management of dentin hypersensitivity and caries after enamel loss.

Important factors involved in odontogenesis in mouse dental papillae disappear between the pre- and post-natal stages of development. Therefore, we hypothesized that certain genes involved in odontogenesis in dental papillae were subject to pre-/post-natal down-regulation. Our goal was to identify, by microarray analysis, which genes were down-regulated. Dental papillae were isolated from embryonic 16-day-, 18-day- (E16, E18), and post-natal 3-day-old (P3) murine first mandibular molar germs and analyzed by microarray. The number of down-regulated genes was 2269 between E16 and E18, and 3130 between E18 and P3. Drastic down-regulation (fold change > 10.0) of Adamts4, Aldha1a2, and Lef1 was observed at both E16 and E18, and quantitative RT-PCR revealed a post-natal reduction in their expression (Adamts4, 1/3; Aldh1a2, 1/13; and Lef1, 1/37). These results suggest that down-regulation of these three genes is an important factor in normal odontogenesis in dental papillae.

In recent years, fluorescent nanodiamond (fND) particles containing nitrogen-vacancy (NV) centers gained recognition as an attractive probe for nanoscale cellular imaging and quantum sensing. For these applications, precise localization of fNDs inside of a living cell is essential. Here we propose such a method by simultaneous detection of the signal from the NV centers and the spectroscopic Raman signal from the cells to visualize the nucleus of living cells. However, we show that the commonly used Raman cell signal from the fingerprint region is not suitable for organelle imaging in this case. Therefore, we develop a method for nucleus visualization exploiting the region-specific shape of C-H stretching mode and further use k -means cluster analysis to chemically distinguish the vicinity of fNDs. Our technique enables, within a single scan, to detect fNDs, distinguish by chemical localization whether they have been internalized into cell and simultaneously visualize cell nucleus without any labeling or cell-fixation. We show for the first time spectral colocalization of unmodified high-pressure high-temperature fND probes with the cell nucleus. Our methodology can be, in principle, extended to any red- and near-infrared-luminescent cell-probes and is fully compatible with quantum sensing measurements in living cells.

Loss of pulp due to caries and pulpitis leads to loss of teeth and reduced quality of life. Thus, there is an unmet need for regeneration of pulp. A promising approach is stem cell therapy. Autologous pulp stem/progenitor (CD105 + ) cells were transplanted into a root canal with stromal cell-derived factor-1 (SDF-1) after pulpectomy in mature teeth with complete apical closure in dogs. The root canal was successfully filled with regenerated pulp including nerves and vasculature by day 14, followed by new dentin formation along the dentinal wall. The newly regenerated tissue was significantly larger in the transplantation of pulp CD105 + cells with SDF-1 compared with those of adipose CD105 + cells with SDF-1 or unfractionated total pulp cells with SDF-1. The pulp CD105 + cells highly expressed angiogenic/neurotrophic factors compared with other cells and localized in the vicinity of newly formed capillaries after transplantation, demonstrating its potent trophic effects on neovascularization. Two-dimensional electrophoretic analyses and real-time reverse transcription–polymerase chain reaction analyses demonstrated that the qualitative and quantitative protein and mRNA expression patterns of the regenerated pulp were similar to those of normal pulp. Thus, this novel stem cell therapy is the first demonstration of complete pulp regeneration, implying novel treatment to preserve and save teeth.

Background Huntington’s disease (HD) is a rare, autosomal dominant neurodegenerative disorder caused by an expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene. It manifests with motor, cognitive, and behavioural impairments, leading to progressive functional decline over approximately 20 years. Despite symptomatic treatments, no approved disease-modifying therapies are currently available, though experimental approaches are under investigation. Recent research has explored human dental pulp stem cells (hDPSCs) as a potential therapeutic approach due to their neurotrophic properties and ability to modulate neuroinflammation. This Phase II trial aimed to evaluate the safety and efficacy of NestaCell®, an allogeneic hDPSC-based therapy, in patients with HD. Methods This randomised, double-blind, placebo-controlled trial included 35 patients assigned at a 2:2:1 ratio to receive hDPSCs at 1 million cells/kg, 2 million cells/kg, or placebo over nine intravenous infusions across 11 months. The primary endpoint was the Unified Huntington’s Disease Rating Scale (UHDRS) Total Motor Score (TMS) change. Secondary outcomes included UHDRS Total Functional Capacity (TFC), Total Chorea Score (TCS), Functional Checklist (FC), and magnetic resonance imaging (MRI) based white matter quantification. Safety was assessed by monitoring treatment-emergent adverse events (TEAEs) and laboratory parameters. Results Both doses demonstrated a favourable safety profile, with no increased incidence of adverse events compared to the placebo. No serious adverse event was deemed related to treatment. Both doses significantly improved UHDRS-TMS compared to placebo ( p  = 0.005), while the 2 million cells/kg group showed significant benefits in UHDRS-TFC ( p  = 0.011). Additional improvements were observed in the TCS and FC, suggesting a broader clinical impact. MRI analysis indicated a non-significant trend toward neuroprotection, with slower central nervous system (CNS) white and grey matter decline in treated patients. Conclusions NestaCell® was well tolerated and showed statistically significant improvements in motor and functional outcomes in HD patients. While MRI trends suggest a potential neuroprotective effect, further investigation is warranted. These findings support the advancement to a Phase III trial to confirm efficacy and long-term safety in a larger cohort. Trial registration : This study was registered on August 16, 2017, at ClinicalTrials.gov (identifier: NCT03252535; https://clinicaltrials.gov/search?cond=NCT03252535 ).

Periodontitis causes the destruction of tooth-supporting tissues, and current therapies for periodontal regeneration are invasive. In this study, a human dental pulp stem cell (DPSC; hDP-MSC) injection was developed to promote periodontal regeneration through a non-invasive procedure. A total of 132 patients with chronic periodontitis (158 teeth) from two centers in China were included. Thirty-six were randomly assigned to different DPSC dose groups (ranging from 1 × 10 6 to 1 × 10 7 DPSCs per tooth, with nine injected with saline only), and 96 were randomly assigned to a single-injection group (1 × 10 7 /0.6 mL DPSCs), a double-injection group (1 × 10 7 /0.6 mL DPSCs × 2), or a saline group, in a 1:1:1 ratio. At 6 months post-therapy, attachment loss (AL), periodontal probing depth (PD), gingival recession (GR), tooth mobility (TM), and bone defect depth (BDD) were examined. The primary outcome was AL. DPSC injection resulted in greater improvement in BDD (0.30 ± 0.484 mm) compared to saline injection (0.04 ± 0.315 mm). Post hoc analysis showed that DPSC injection had significantly better outcomes in patients with stage III periodontitis (AL ≥ 5 mm): 54 patients received DPSCs, and 40 received saline. AL improved by 1.67 ± 1.508 mm in the DPSC group (26.81% improvement) and by 1.03 ± 1.310 mm in the saline group (17.43% improvement). The therapeutic effects encompassed improvements in both soft and hard tissues. In summary, DPSC injection was safe and improved clinical outcomes compared to saline injection in patients with stage III periodontitis. Larger trials are warranted to validate these findings (ClinicalTrials.gov registration: NCT05924373).

Autologous transplantation of pulp stem cells with granulocyte‐colony stimulating factor (G‐CSF) in a dog pulpectomized tooth yielded better effects than transplantation of G‐CSF or pulp stem cells alone. The combinatorial trophic effects of pulp stem cells and G‐CSF are of immediate utility for pulp/dentin regeneration, demonstrating the prerequisites of safety and efficacy critical for clinical applications. Treatment of deep caries with pulpitis is a major challenge in dentistry. Stem cell therapy represents a potential strategy to regenerate the dentin‐pulp complex, enabling conservation and restoration of teeth. The objective of this study was to assess the efficacy and safety of pulp stem cell transplantation as a prelude for the impending clinical trials. Clinical‐grade pulp stem cells were isolated and expanded according to good manufacturing practice conditions. The absence of contamination, abnormalities/aberrations in karyotype, and tumor formation after transplantation in an immunodeficient mouse ensured excellent quality control. After autologous transplantation of pulp stem cells with granulocyte‐colony stimulating factor (G‐CSF) in a dog pulpectomized tooth, regenerated pulp tissue including vasculature and innervation completely filled in the root canal, and regenerated dentin was formed in the coronal part and prevented microleakage up to day 180. Transplantation of pulp stem cells with G‐CSF yielded a significantly larger amount of regenerated dentin‐pulp complex compared with transplantation of G‐CSF or stem cells alone. Also noteworthy was the reduction in the number of inflammatory cells and apoptotic cells and the significant increase in neurite outgrowth compared with results without G‐CSF. The transplanted stem cells expressed angiogenic/neurotrophic factors. It is significant that G‐CSF together with conditioned medium of pulp stem cells stimulated cell migration and neurite outgrowth, prevented cell death, and promoted immunosuppression in vitro. Furthermore, there was no evidence of toxicity or adverse events. In conclusion, the combinatorial trophic effects of pulp stem cells and G‐CSF are of immediate utility for pulp/dentin regeneration, demonstrating the prerequisites of safety and efficacy critical for clinical applications.

Odontoblasts function as mechanosensory receptors because of the expression of mechanosensitive channels in these cells. However, it is unclear if odontoblasts direct the signal transmission evoked by heat/cold or osmotic changes. This study investigated the effects of heat/cold or osmotic changes on calcium signaling and the functional expression of the thermo/mechanosensitive transient receptor potential (TRP) channels in primary cultured mouse odontoblastic cells, with the use of RT-PCR, fluorometric calcium imaging, and electrophysiology. TRPV1, TRPV2, TRPV3, TRPV4, and TRPM3 mRNA was expressed, but TRPM8 and TRPA1 mRNA was not. The receptor-specific stimulation of TRPV1-3 (heat-sensing receptors) and TRPV4/ TRPM3 (mechanic receptors) caused increases in the intracellular calcium concentration. Moreover, the channel activities of TRPV1-4 and TRPM3 were confirmed by a whole-cell patch-clamp technique. These results suggest that primary cultured mouse odontoblasts express heat/mechanosensitive TRP channels and play a role in the underlying mechanisms of thermo/mechanosensitive sensory transmission.