Biomaterial design for regenerating aged bone: materiobiological advances and paradigmatic shifts.

China's aging demographic poses a challenge for treating prevalent bone diseases impacting life quality. As bone regeneration capacity diminishes with age due to cellular dysfunction and inflammation, advanced biomaterials-based approaches offer hope for aged bone regeneration. This review synthesizes materiobiology principles, focusing on biomaterials that target specific biological functions to restore tissue integrity. It covers strategies for stem cell manipulation, regulation of the inflammatory microenvironment, blood vessel regeneration, intervention in bone anabolism and catabolism, and nerve regulation. The review also explores molecular and cellular mechanisms underlying aged bone regeneration and proposes a database-driven design process for future biomaterial development. These insights may also guide therapies for other age-related conditions, contributing to the pursuit of 'healthy aging'.

In Vivo Osteo-organoid Approach for Harvesting Therapeutic Hematopoietic Stem/Progenitor Cells.

Hematopoietic stem cell transplantation (HSCT) requires a sufficient number of therapeutic hematopoietic stem/progenitor cells (HSPCs). To identify an adequate source of HSPCs, we developed an in vivo osteo-organoid by implanting scaffolds loaded with recombinant human bone morphogenetic protein-2 (rhBMP-2) into an internal muscle pouch near the femur in mice. After 12 weeks of implantation, we retrieved the in vivo osteo-organoids and conducted flow cytometry analysis on HPSCs, revealing a significant presence of HSPC subsets within the in vivo osteo-organoids. We then established a sublethal model of hematopoietic/immune system injury in mice through radiation and performed hematopoietic stem cell transplantation (HSCT) by injecting the extracted osteo-organoid-derived cells into the peripheral blood of radiated mice. The effect of hematopoietic recovery was evaluated through hematological, peripheral blood chimerism, and solid organ chimerism analyses. The results confirmed that in vivo osteo-organoid-derived cells can rapidly and efficiently reconstruct damaged peripheral and solid immune organs in irradiated mice. This approach holds potential as an alternative source of HSPCs for HSCT, offering benefits to a larger number of patients.

The discrimination between autoimmune glial fibrillary acidic protein astrocytopathy and tuberculous meningitis.

OBJECTIVE: The differential diagnosis between autoimmune glial fibrillary acidic protein astrocytopathy (AGFAPA) mimicking tuberculous meningitis and tuberculous meningitis (TBM) remains challenging in clinical practice. This study aims to identify the clinical, laboratory parameters, and clinical score systems that may be helpful in differentiating AGFAPA from TBM. METHOD: Overall 22 AGFAPA patients who were initially misdiagnosed as TBM (AGFAPA-TBM) and 30 confirmed TBM patients were included. The clinical, laboratory, imaging parameters, Thwaites systems, and Lancet consensus scoring systems (LCSS) of all patients were reviewed. Logistic regression was employed to establish a diagnostic formula to differentiate AGFAPA-TBM from TBM. The receiver operating characteristic (ROC) curve was applied to determine the best diagnostic critical point of the formula. RESULTS: Urinary retention was more frequent in AGFAPA-TBM patients (72.7% vs 33.3%, p = 0.012). A significantly lower ratio of T-SPOT. TB was noted in AGFAPA-TBM patients (9.1% vs 82.1%, p < 0.001). We found the LCSS was able to differentiate AGFAPA-TBM from TBM (AUC value 0.918, 95% CI=0.897-0.924). Furthermore, we set up a new scoring system with three variables: urinary retention, T-SPOT. TB, and cerebral imaging criteria in LCSS. The proposed diagnostic score ranges from -8 to 2, and a score of ≥ 0 was suggestive of AGFAPA-TBM (AUC value 0.938, 95% CI=0.878-0.951). CONCLUSIONS: This study is the first to evaluate the Thwaites system and LCSS in AGFAPA-TBM and TBM. We provide an alternative diagnostic formula to differentiate AGFAPA-TBM from TBM and suggest testing for GFAP antibodies to avoid misdiagnosis when this scoring system meets AGFAPA-TBM.

Impact of inflammation and the immune system on hepatocellular carcinoma recurrence after hepatectomy.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Hepatectomy remains the first-line treatment for patients with resectable HCC. However, the reported recurrence rate of HCC at 5 years after surgery is between 50% and 70%. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease are well-known risk factors for recurrence after treatment. In addition to tumor-related factors, ever-increasing amounts of studies are finding that the tumor microenvironment also plays an important role in the recurrence of HCC, including systemic inflammatory response and immune regulation. Based on this, some inflammatory and immune markers were used in predicting postoperative cancer recurrence. These include neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, cytotoxic T cells, and regulatory T cells, among others. In this review, we summarized the inflammatory and immune markers that affect recurrence after HCC resection in order to provide direction for adjuvant therapy after HCC resection and ultimately achieve the goal of reducing recurrence.

Biomaterial-assisted therapeutic cell production and modification in vivo.

Hematopoietic stem cell transplantation remains the preferred treatment for a variety of hematopoietic function disorders. To address the issue of limited numbers of hematopoietic stem/progenitor cells (HSPCs), significant progress has been made in the technology for ex vivo expansion of HSPCs. In addition, biomaterial-assisted in vivo production technology for therapeutic cells, including HSPCs, is gradually gaining attention. With the aid of specifically functional biomaterials, researchers can construct bone-like tissues exhibiting typical bone marrow-like structures (termed in vivo osteo-organoids in this article) for the production of therapeutic cells. These in vivo osteo-organoids mimic the native bone marrow niche and provide a microenvironment conducive to the expansion and differentiation of HSPCs. In this perspective article, we systematically summarize the history of in vivo osteo-organoids as a model for studying hematopoiesis and cancer metastasis and propose the challenges faced by the in vivo osteo-organoid production platform for therapeutic cells in terms of clinical translation. Ultimately, we hope to achieve functional customization of in vivo osteo-organoid-derived cells through continuously developed material design methods, so as to meet the treatment needs of different types of diseases and bring hope for life to more people.

Manganese accumulation in red blood cells as a biomarker of manganese exposure and neurotoxicity.

Although overexposure to manganese (Mn) is known to cause neurotoxic damage, effective exposure markers for assessing Mn loading in Mn-exposed workers are lacking. Here, we construct a Mn-exposed rat model to perform correlation analysis between Mn-induced neurological damage and Mn levels in various biological samples. We combine this analysis with epidemiological investigation to assess whether Mn concentrations in red blood cells (MnRBCs) and urine (MnU) can be used as valid exposure markers. The results show that Mn exposure resulted in neurotoxic damage in rats and that MnRBCs correlated well with neurological damage, showing potential as a novel Mn exposure biomarker. These findings provide a basis for health monitoring of Mn-exposed workers and the development of more appropriate biological exposure limits.

Background-Free and Reversible Upconversion Hydrogel Sensing Platform for Visual Monitoring of Sulfite.

Excessive sulfite usage in food and pharmaceutical production causes respiratory and neurological diseases, underscoring the need for a sensitive and rapid quantification strategy. The portable sensing platform based on a luminescent hydrogel sensor is a powerful tool for the on-site, real-time detection of sulfite ions. However, the lack of recyclability in almost all reaction-based hydrogel sensors increases the application cost. This study constructed a reversible and upconversion nanoprobe combining upconversion nanoparticles (UCNPs) and pararosaniline (PAR) for sulfite detection. The upconversion nanoprobe was further encapsulated in a three-dimensional polyacrylamide hydrogel matrix to create a background-free, reversible hydrogel sensor. The near-infrared excitation of UCNPs avoids the autofluorescence in the hydrogel and real samples. Meanwhile, PAR serves as a specific recognition unit for sulfite ions. After the addition of sulfites, a specific reaction occurs between PAR and sulfites, leading to the recovery of characteristic emission at 540 nm, achieving sensitive detection of sulfite ions. Importantly, this specific reaction is reversible under thermal treatment, allowing the hydrogel sensor to return to its initial state and thus enabling reversible detection of sulfite ions. Furthermore, a portable sensing platform is developed to realize point-of-care, real-time quantitative detection of sulfite ions. The proposed upconversion reversible hydrogel sensor provides a new sensing strategy for the detection of hazardous substances in food and offers new insights into the preparation of reversible, highly sensitive hydrogel sensors.

Analysis of the relationship between drug susceptibility of Cryptococcus neoformans isolates and mortality in HIV-negative cryptococcal meningitis.

OBJECTIVES: The relationship between antifungal susceptibility and mortality of cryptococcal meningitis (CM) in HIV-negative patients is poorly understood. METHODS: We conducted a retrospective analysis of 1-year follow-up of 200 HIV-negative CM patients with an initial cerebrospinal fluid (CSF) culture for Cryptococcus neoformans. According to the cut-off values of minimum inhibitory concentration (MIC), two groups of five antifungal agents were classified: amphotericin B (AmB), ≤0.5 µg/mL, >0.5 µg/mL; 5-flucytosine (5-FC), ≤4 µg/mL, >4 µg/mL; fluconazole (FLU), ≤4 µg/mL, >4 µg/mL; itraconazole (ITR), ≤0.125 µg/mL, >0.125 µg/mL; and voriconazole (VOR), <0.25 µg/mL, ≥0.25 µg/mL. Comparisons were performed to analyse clinical features, laboratory, modified Rankin Scale (mRS) scores, and CSF findings under different prognosis outcomes in 1-year. RESULTS: All of Cryptococcus neoformans isolates were sensitive to AmB and VOR, most of them were sensitive to 5-FC and FLU (95.5% and 90.5%, respectively) while only 55.0% of them were susceptible to ITR. Minimum inhibitory concentrations of ITR and VOR were significantly related to baseline mRS scores. All-cause mortality was not significantly related to MICs in Cryptococcus neoformans strains. The combination of actual antifungal agents and two groups of the MICs values for antifungal agents had no significant effects on all-cause mortality. CONCLUSION: Most Cryptococcus neoformans isolates were sensitive to AmB, VOR, 5-FC, and FLU. Because of the small number of deaths, we are not able to comment on whether MIC is associated with mortality of CM in HIV-negative patients.

Inhibition of cGAS-STING pathway by stress granules after activation of M2 macrophages by human mesenchymal stem cells against drug induced liver injury.

OBJECTIVE: Cells can produce stress granules (SGs) to protect itself from damage under stress. The cGAS-STING pathway is one of the important pattern recognition pathways in the natural immune system. This study was investigated whether human mesenchymal stem cells (hMSCs) could protect the liver by inducing M2 macrophages to produce SGs during acute drug induced liver injury (DILI) induced by acetaminophen (APAP). METHODS: After intragastric administration of APAP in vivo to induce DILI mice model, hMSCs were injected into the tail vein. The co-culture system of hMSCs and M2 macrophages was established in vitro. It was further use SGs inhibitor anisomicin to intervene M2 macrophages. The liver histopathology, liver function, reactive oxygen species (ROS) level, apoptosis pathway, endoplasmic reticulum stress (ERS) level, SGs markers (G3BP1/TIA-1), cGAS-STING pathway, TNF-α, IL-6, IL-1ß mRNA levels in liver tissue and M2 macrophages were observed. RESULTS: In vivo experiments, it showed that hMSCs could alleviate liver injury, inhibite the level of ROS, apoptosis and ERS, protect liver function in DILI mice. The mount of M2 was increased in the liver. hMSCs could also induce the production of SGs, inhibit the cGAS-STING pathway and reduce TNF-α, IL-6, IL-1ß mRNA expression. The results in vitro showed that hMSCs could induce the production of SGs in macrophages, inhibit the cGAS-STING pathway, promote the secretion of IL-4 and IL-13, and reduce TNF-α, IL-6, IL-1ß mRNA level in cells. In the process of IL-4 inducing M2 macrophage activation, anisomycin could inhibit the production of SGs, activate the cGAS-STING pathway, and promote the inflammatory factor TNF-α, IL-6, IL-1ß mRNA expression in cells. CONCLUSIONS: HMSCs had a protective effect on acute DILI in mice induced by APAP. Its mechanism might involve in activating M2 type macrophages, promoting the production of SGs, inhibiting the cGAS-STING pathway, and reducing the expression of pro-inflammatory factors in macrophages, to reduce hepatocytes damage.

Sulfated oligosaccharide activates endothelial Notch for inducing macrophage-associated arteriogenesis to treat ischemic diseases.

Ischemic diseases lead to considerable morbidity and mortality, yet conventional clinical treatment strategies for therapeutic angiogenesis fall short of being impactful. Despite the potential of biomaterials to deliver pro-angiogenic molecules at the infarct site to induce angiogenesis, their efficacy has been impeded by aberrant vascular activation and off-target circulation. Here, we present a semisynthetic low-molecular sulfated chitosan oligosaccharide (SCOS) that efficiently induces therapeutic arteriogenesis with a spontaneous generation of collateral circulation and blood reperfusion in rodent models of hind limb ischemia and myocardial infarction. SCOS elicits anti-inflammatory macrophages' (Mφs') differentiation into perivascular Mφs, which in turn directs artery formation via a cell-to-cell communication rather than secretory factor regulation. SCOS-mediated arteriogenesis requires a canonical Notch signaling pathway in Mφs via the glycosylation of protein O-glucosyltransferases 2, which results in promoting arterial differentiation and tissue repair in ischemia. Thus, this highly bioactive oligosaccharide can be harnessed to direct efficiently therapeutic arteriogenesis and perfusion for the treatment of ischemic diseases.

Clinical characteristics, treatment, and outcome of low-risk non-HIV-associated cryptococcal meningitis: A retrospective cohort study.

Although non-human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) is a severe disease, there are still some non-HIV CM patients with a low risk of therapeutic failure. Recognizing clinical characteristics of low-risk non-HIV-associated CM may enable clinicians to treat non-HIV-associated CM more reasonably. According to the definition of low-risk non-HIV-associated CM in the 2010 Infectious Diseases Society of America guideline, a total of 220 non-HIV CM patients were divided into two groups (Group 1: 35 low-risk patients and Group 2: 185 non-low-risk patients). Clinical characteristics, treatment, and outcome were compared between the two groups. Compared with non-low-risk patients, low-risk patients had a lower rate of headache (82.9% vs. 95.7%, P = .012), cerebrospinal fluid (CSF) opening pressure (OP) at baseline (CSF OP < 250-mm H2O, 60.0% vs. 32.4%, P = .001), and baseline CSF cryptococcal count (median, 0 vs. 2376, P < .001), higher baseline CSF white blood cell (median, 130 vs. 90, P = .029) and CSF protein (median, 0.87 vs. 0.73, P = .011). Multivariate analysis showed that baseline CSF OP <250-mm H2O (OR: 2.545, 95% CI 1.168, 5.545, P = .019) was independently associated with low-risk for non-HIV-associated CM. The lengths of AMB-d-based induction therapy of low-risk patients (median, 20 days) were shorter (P < .001) than that of non-low-risk patients (median, 38 days). The successful outcome rate of low-risk patients was higher than non-low-risk patients (97.1% vs. 54.6%, P < .001). We demonstrated that non-HIV-associated CM patients with baseline CSF OP < 250-mm H2O were prone to the low-risk status.

This was a retrospective cohort study to find the features of low-risk non-human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM). We found that non-HIV-associated CM patients with baseline cerebrospinal fluid opening pressure <250-mm H2O were prone to low-risk status.

Exploring Shared Genetic Signatures of Alzheimer's Disease and Multiple Sclerosis: A Bioinformatic Analysis Study.

INTRODUCTION: Many clinical studies reported the coexistence of Alzheimer's disease (AD) and multiple sclerosis (MS), but the common molecular signature between AD and MS remains elusive. The purpose of our study was to explore the genetic linkage between AD and MS through bioinformatic analysis, providing new insights into the shared signatures and possible pathogenesis of two diseases. METHODS: The common differentially expressed genes (DEGs) were determined between AD and MS from datasets obtained from Gene Expression Omnibus (GEO) database. Further, functional and pathway enrichment analysis, protein-protein interaction network construction, and identification of hub genes were carried out. The expression level of hub genes was validated in two other external AD and MS datasets. Transcription factor (TF)-gene interactions and gene-miRNA interactions were performed in NetworkAnalyst. Finally, receiver operating characteristic (ROC) curve analysis was applied to evaluate the predictive value of hub genes. RESULTS: A total of 75 common DEGs were identified between AD and MS. Functional and pathway enrichment analysis emphasized the importance of exocytosis and synaptic vesicle cycle, respectively. Six significant hub genes, including CCL2, CD44, GFAP, NEFM, STXBP1, and TCEAL6, were identified and verified as common hub genes shared by AD and MS. FOXC1 and hsa-mir-16-5p are the most common TF and miRNA in regulating hub genes, respectively. In the ROC curve analysis, all hub genes showed good efficiency in helping distinguish patients from controls. CONCLUSION: Our study first identified a common genetic signature between AD and MS, paving the road for investigating shared mechanism of AD and MS.

Seasonality and meteorological factors of HIV-negative cryptococcal meningitis in Guangdong Province, China.

OBJECTIVE: Information about the seasonal characteristics of human immunodeficiency virus (HIV)-negative cryptococcal meningitis (CM) is quite limited. The aim of this study was to explore the seasonality and meteorological factors of HIV-negative patients with CM. METHODS: We performed a retrospective study of 469 HIV-negative CM patients admitted to the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China. Their initial onset symptoms of CM occurred from January 2011 to December 2020. The temperature, precipitation, sunlight, humidity and wind speed for the corresponding period and the associated topographic, ecological type and soil type parameters data were collected. The Poisson regression model was used to determine the meteorological factors associated with CM onset. The geographical detector method was used to detect other environmental factors associated with CM onset. RESULTS: CM onset did not showed a seasonal fluctuation, but was strongly associated with mean temperature (ß = .010, p = .028) and mean relative humidity (ß = -.011, p = .006). In the rainy season, only mean wind speed remained significantly associated with CM onset (ß = -.108, p = .041). In the dry season, mean temperature (ß = .014, p = .016), mean relative humidity (ß = -.016, p = .006) and hours of sunlight (ß = -.002, p = .016) were significantly associated with CM onset. Topographic, ecological type and soil type factors did not add explanatory power. CONCLUSIONS: Our findings add the knowledge about the environmental factors of HIV-negative CM. Meteorological factors, especially temperature and humidity, may be the main environmental factors affecting the onset of HIV-negative CM.

Anisotropic Phonon Behavior and Phase Transition in Monolayer ReSe2 Discovered by High Pressure Raman Scattering.

Re-based transition metal dichalcogenides have attracted extensive attention owing to their anisotropic structure and excellent properties in applications such as optoelectronic devices and electrocatalysis. The present study methodically investigated the evolution of specific Raman phonon mode behaviors and phase transitions in monolayer and bulk ReSe2 under high pressure. Considering the distinctive anisotropic characteristics and the vibration vectors of Re and Se atoms exhibited by monolayer ReSe2, we perform phonon dispersion calculations and propose a methodology utilizing pressure-dependent polarized Raman measurements to explore the precise structural evolution of monolayer ReSe2 under the stress fields. Varied behaviors of the Eg-like and Ag-like modes, along with their specific vector transformations, have been identified in the pressure range 0-14.59 GPa. The present study aims to offer original perspectives on the physical evolution of Re-based transition metal dichalcogenides, elucidating their fundamental anisotropic properties and exploring potential applicability in diverse devices.

Advancements in mesenchymal stem cell therapy for liver cirrhosis: Unveiling origins, treatment mechanisms, and current research frontiers.

Chronic liver disease inevitably progresses to liver cirrhosis, significantly compromising patients' overall survival and quality of life. However, a glimmer of hope emerges with the emergence of mesenchymal stem cells, possessing remarkable abilities for self-renewal, differentiation, and immunomodulation. Leveraging their potential, MSCs have become a focal point in both basic and clinical trials, offering a promising therapeutic avenue to impede fibrosis progression and enhance the life expectancy of individuals battling hepatic cirrhosis. This comprehensive review serves to shed light on the origin of MSCs, the intricate mechanisms underlying cirrhosis treatment, and the cutting-edge advancements in basic and clinical research surrounding MSC-based therapies for liver cirrhosis patients.

Human umbilical cord-derived mesenchymal stromal cells alleviate liver cirrhosis through the Hippo/YAP/Id1 pathway and macrophage-dependent mechanism.

BACKGROUND: Few effective anti-fibrotic therapies are currently available for liver cirrhosis. Mesenchymal stromal cells (MSCs) ameliorate liver fibrosis and contribute to liver regeneration after cirrhosis, attracting much attention as a potential therapeutic strategy for the disease. However, the underlying molecular mechanism of their therapeutic effect is still unclear. Here, we investigated the effect of human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) in treating liver cirrhosis and their underlying mechanisms. METHODS: We used carbon tetrachloride (CCl4)-induced mice as liver cirrhosis models and treated them with hUC-MSCs via tail vein injection. We assessed the changes in liver function, inflammation, and fibrosis by histopathology and serum biochemistry and explored the mechanism of hUC-MSCs by RNA sequencing (RNA-seq) using liver tissues. In addition, we investigated the effects of hUC-MSCs on hepatic stellate cells (HSC) and macrophages by in vitro co-culture experiments. RESULTS: We found that hUC-MSCs considerably improved liver function and attenuated liver inflammation and fibrosis in CCl4-injured mice. We also showed that these cells exerted therapeutic effects by regulating the Hippo/YAP/Id1 axis in vivo. Our in vitro experiments demonstrated that hUC-MSCs inhibit HSC activation by regulating the Hippo/YAP signaling pathway and targeting Id1. Moreover, hUC-MSCs also alleviated liver inflammation by promoting the transformation of macrophages to an anti-inflammatory phenotype. CONCLUSIONS: Our study reveals that hUC-MSCs relieve liver cirrhosis in mice through the Hippo/YAP/Id1 pathway and macrophage-dependent mechanisms, providing a theoretical basis for the future use of these cells as a potential therapeutic strategy for patients with liver cirrhosis.

IGF2-NR4A2 Signaling Regulates Macrophage Subtypes to Attenuate Liver Cirrhosis.

Background and Aims: Liver cirrhosis can lead to liver failure and eventually death. Macrophages are the main contributors to cirrhosis and have a bidirectional role in regulating matrix deposition and degradation. Macrophage-based cell therapy has been developed as an alternative to liver transplantation. However, there is insufficient evidence regarding its safety and efficacy. In this study, we aimed to explore the effect of combining insulin-like growth factor 2 (IGF2) with bone marrow-derived macrophages (BMDMs) to treat mice with liver cirrhosis. Methods: We assessed liver inflammation, fibrosis regression, liver function, and liver regeneration in mice with CCl4-induced cirrhosis and treated with BMDM only or IGF2 + BMDM. We performed in vitro experiments in which activated hepatic stellate cells (HSCs) were co-cultured with macrophages in the presence or absence of IGF2. The polarity of macrophages and the degree of inhibition of HSCs were examined. The effect of IGF2 on macrophages was also verified by the overexpression of IGF2. Results: Combining IGF2 with BMDM reduced liver inflammation and fibrosis and increased hepatocyte proliferation. Combining IGF2 with BMDM was more effective than using BMDM alone. In vitro experiments demonstrated that IGF2 inhibited HSCs activation by upregulating NR4A2 to promote the anti-inflammatory macrophages phenotype. IGF2 also increased the synthesis of matrix metalloproteinases (MMPs) by macrophages, which may explain why administering IGF2 combined with BMDM was more effective than administering BMDM only. Conclusions: Our study provides a theoretical basis for the future use of BMDM-based cell therapy to treat liver cirrhosis.

Neurological worsening during treatment of HIV-negative cryptococcal meningitis in a patient with Evans syndrome.

A 49-year-old woman with a rare autoimmune hematological disease, Evans syndrome, was admitted to the authors' hospital with immune reconstitution inflammatory syndrome-like reconstitution syndrome after effective antifungal therapy for cryptococcal meningitis. She initially improved after receiving corticosteroid treatment; after prednisone was tapered, her clinical presentation and brain imaging deteriorated but finally improved with the addition of thalidomide. Immune reconstitution inflammatory syndrome-like reconstitution syndrome is a rare complication in cryptococcal meningitis patients receiving immunosuppressive therapy. Thalidomide can be given in addition to corticosteroid therapy to effectively control the paradoxical inflammatory response and improve clinical outcomes.

Sulfated Polysaccharide Regulates the Homing of HSPCs in a BMP-2-Triggered In Vivo Osteo-Organoid.

Hematopoietic stem cell transplantation (HSCT) is a well-established method for a variety of acquired and congenital diseases. However, the limited number and sources of therapeutic hematopoietic stem/progenitor cells (HSPCs) hinder the further application of HSCT. A BMP-2 triggered in vivo osteo-organoid that is previously reported, serves as a kind of stem cell biogenerator, for obtaining therapeutic HSPCs via activating the residual regenerative capacity of mammals using bioactive biomaterials. Here, it is demonstrated that targeting the homing signaling of HSPCs elevates the proportions and biological functions of HSPCs in the in vivo osteo-organoid. Notably, it is identified that sulfonated chito-oligosaccharide, a degradation product of sulfonated chitosan, specifically elevates the expression of endothelial protein C receptor on HSPCs and vascular cell adhesion molecule-1 on macrophages in the in vivo osteo-organoid, ultimately leading to the production of adequate therapeutic HSPCs. This in vivo osteo-organoid approach has the potential to provide an alternative HSPCs source for HSCT and benefits more patients.