Acta Biomaterialia
·
2024
·
IF 9.4
Jianxin Hao,Xiaopeng Yu,Kai Tang,Xueru Ma,Hongxu Lu,Chengtie Wu
Recent advances in bone tissue engineering have shown promise for bone repair post osteosarcoma excision. However, conflicting research on mesenchymal stem cells (MSCs) has raised concerns about their potential to either promote or inhibit tumor cell proliferation. It is necessary to thoroughly understand the interactions between MSCs and tumor cells. Most previous studies only focused on the interactions between cells within the tumor tissues. It has been challenging to develop an in vitro model of osteosarcoma excision sites replicating the complexity of the bone microenvironment and cell distribution. In this work, we designed and fabricated modular bioceramic scaffolds to assemble into a co-culture model. Because of the bone-like composition and mechanical property, tricalcium phosphate bioceramic could mimic the bone microenvironment and recapitulate the cell-extracellular matrix interaction. Moreover, the properties for easy assembly enabled the modular units to mimic the spatial distribution of cells in the osteosarcoma excision site. Under this co-culture model, MSCs showed a noticeable tumor-stimulating effect with a potential risk of tumor recurrence. In addition, tumor cells also could inhibit the osteogenic ability of MSCs. To undermine the stimulating effects of MSCs on tumor cells, we present the methods of pre-differentiated MSCs, which had lower expression of IL-8 and higher expression of osteogenic proteins. Both in vitro and in vivo studies confirm that pre-differentiated MSCs could maintain high osteogenic capacity without promoting tumor growth, offering a promising approach for MSCs’ application in bone regeneration. Overall, 3D modular scaffolds provide a valuable tool for constructing hard tissue in vitro models. Statement of significance Bone tissue engineering using mesenchymal stem cells (MSCs) and biomaterials has shown promise for bone repair post osteosarcoma excision. However, conflicting researches on MSCs have raised concerns about their potential to either promote or inhibit tumor cell proliferation. It remains challenges to develop in vitro models to investigate cell interactions, especially of osteosarcoma with high hardness and special composition of bone tissue. In this work, modular bioceramic scaffolds were fabricated and assembled to co-culture models. The interactions between MSCs and MG-63 were manifested as tumor-stimulating and osteogenesis-inhibiting, which means potential risk of tumor recurrence. To undermine the stimulating effect, pre-differentiation method was proposed to maintain high osteogenic capacity without tumor-stimulating, offering a promising approach for MSCs’ application in bone regeneration.
研究领域:
组织工程
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癌症生物学
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干细胞研究
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生物材料科学
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DOI
PubMed
高影响因子
EUROPEAN POLYMER JOURNAL
·
2022
·
IF 5.546
Weiyue Song,Ziyang Jin,Xing Huang,Zhenhao Xi,Xusong Luo,Lian Cen
This study was aimed to develop a capillary-based microfluidic methodology for preparing poly (lactic-co-glycolic acid) (PLGA) microcarriers patterned with collagen patchy structure (PLGA-Col), which are superior in enhancing proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs) seeded on them. Primary W/O emulsions were first prepared using aqueous collagen and PLGA solutions. A two-phase microfluidic device was then designed and the emulsions were used as the inner liquid phase to obtain PLGA-Col microcarriers. The content of collagen was varied to yield PLGA-Col-L (lower collagen content) and PLGA-Col-H (higher collagen content). The proliferation behavior of the cells on the microcarriers was evaluated by live/dead cell staining and CCK-8 assays, while the osteogenic differentiation behavior was evaluated by ALP and qRT-PCR assays. Pristine PLGA microcarriers were also prepared to serve as a control. Three groups, PLGA, PLGA-Col-L, and PLGA-Col-H were then obtained. PLGA-Col was asymmetric with a rough/porous collagen patchy structure. All of these microcarriers could maintain morphology integrity for at least 3 weeks in the aqueous medium before undergoing obvious swelling (5w) and further erosion (7w). It was demonstrated that PLGA-Col could not only enhance the MSCs adhesion/proliferation but also mediate their subsequent osteogenic differentiation. PLGA-Col-L was suitable for supporting the MSCs proliferation, while PLGA-Col-H was more efficient in promoting the osteogenic differentiation of MSCs. Hence, the incorporation of collagen as a patchy structure into PLGA microspheres through the current microfluidic method could be an effective strategy to provide a superior type of microcarriers with well-defined functionality.
研究领域:
组织工程
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生物医学工程
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细胞生物学
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产品关联
DOI
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2022
·
IF 6.064
Li Hui,He Zihao,Li Wenjing,Li Jiao Jiao,Lin Jianhao,Xing Dan
Bone regeneration strategies based on mesenchymal stem cell (MSC) therapy have received widespread attention. Although MSC incorporation into bone scaffolds can help with the repair process, a large number of studies demonstrate variable effects of MSCs with some noting that the inclusion of MSCs does not provide better outcomes compared to unseeded scaffolds. This may in part be related to low cell survival following implantation and/or limited ability to continue with osteogenic differentiation for pre-differentiated cells. In this study, we incorporated MSCs into gelatin microcryogels to form microtissues, and subjected these microtissues to osteogenic induction. We then mixed as-formed microtissues with those subjected to 6 days of osteogenic induction in different ratios, and investigated their ability to induce in vitro and in vivo osteogenesis during self-assembly. Using a full-thickness rat calvarial defect model, we found that undifferentiated and osteogenically induced microtissues mixed in a ratio of 2:1 produced the best outcomes of bone regeneration. This provides a new, customizable cell-based therapeutic strategy for in vivo repair of bone defects.
研究领域:
组织工程
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干细胞生物学
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再生医学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Nano Today
·
2022
·
IF 18.962
Haofang Zhu,Bin Kong,Min Nie,Cheng Zhao,Rui Liu,Ying Xie,Yuanjin Zhao,Lingyun Sun
Mesenchymal stem cells (MSCs) transplantation is an emerging and attractive therapy for immune dysregulation diseases like systemic lupus erythematosus (SLE). However, its application is hindered by short in vivo persistence and poor cellular survival after injection. Here, inspired by the native extracellular matrix (ECM) composition , we presented a novel peptide dendrimer-based microgel encapsulated with MSCs via a microfluidic approach for SLE treatment. By varying microfluidic parameters, monodisperse microgels with tunable diameters, porous microstructures, mechanical stiffness, and immune-isolation potential could be precisely achieved. As the water polymerization environment and ECM like components, the resultant microgels exhibited minimal toxicity in vivo and in vitro. We have also demonstrated that the MSCs encapsulated microgels could significantly increase the cellular bioactivity , enhance the immunomodulatory function, and attenuate disease symptoms in MRL/lpr mice. These results indicate the bioinspired microgels with MSCs encapsulation have potential clinical values in the treatment of SLE and other immune dysregulation diseases.
研究领域:
生物材料
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干细胞治疗
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免疫学
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生物医学工程
✓ 已验证
DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-18
·
IF 10.6
Wu Cheng,Yan Jing,Ge Chenglong,Xie Lucheng,He Yunjie,Zhao Ziyin,Deng Yekun,Dong Qirong,Yin Lichen
The fracture healing outcome is largely dependent on the quantities as well as osteogenic differentiation capacities of mesenchymal stem cells (MSCs) at the lesion site. Herein, macrophage membrane (MM)-reversibly cloaked nanocomplexes (NCs) are engineered for the lesion-targeted and hierarchical co-delivery of short stromal derived factor-1α peptide (sSDF-1α) and Ckip-1 small interfering RNA (Ckip-1 siRNA, siCkip-1) to promote bone repair by concurrently fostering recruitment and osteogenic differentiation of endogenous MSCs. To construct the NCs, a membrane-penetrating α-helical polypeptide first assembles with siCkip-1, and the cationic NCs are sequentially coated with catalase and an outer shell of sSDF-1α-anchored MM. Due to MM-assisted inflammation homing, intravenously injected NCs could efficiently accumulate at the fractured femur, where catalase decomposes the local hydrogen peroxide to generate oxygen bubbles that drives the shedding of sSDF-1α-anchored MM in the extracellular compartment. The exposed, cationic inner core thus enables robust trans-membrane delivery into MSCs to induce Ckip-1 silencing. Consequently, sSDF-1α-guided MSCs recruitment cooperates with siCkip-1-mediated osteogenic differentiation to facilitate bone formation and accelerate bone fracture healing. This study provides an enlightened strategy for the hierarchical co-delivery of macromolecular drugs into different cellular compartments, and it also renders a promising modality for the management of fracture healing.
研究领域:
纳米技术
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再生医学
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生物材料
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干细胞生物学
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药学
✓ 已验证
DOI
PubMed
高影响因子
Small
·
2022
·Vol. 18
·期 36
·2200858
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IF 15.153
Jinglin Wang,Danqing Huang,Haozhen Ren,Luoran Shang
Mesenchymal stem cells (MSCs) have a demonstrated value for acute liver failure (ALF) regeneration, while their delivery stratagems with long-term biological functions, low immune response, and high biocompatibility are still a challenge. Here, a lipopolysaccharide (LPS)-loaded photoresponsive cryogel porous microcarrier (CPM) for MSCs delivery and colonization is presented to promote defect liver regeneration. The CPMs are fabricated with graphene oxide, poly( N -isopropylacrylamide), and gelatin methacrylate (GelMA) via droplet microfluidic technology and a gradient-cooling procedure. Benefitting from the biocompatible GelMA component and the porous microstructure of the CPMs, MSCs can be nondestructively captured and abundantly delivered. Because the LPS can be released from the CPMs under NIR irradiation, the delivered MSCs are imparted with the feature of “trained immunity.” Thus, when the MSCs-laden CPMs are tailored into the liver matched patches by bioprinting and applied in ALF rats, they display superior anti-inflammatory and more significant liver regeneration properties than the untrained MSCs. These features make the CPMs an excellent MSCs delivery system for clinical applications in tissue repair.
研究领域:
组织工程
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干细胞生物学
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生物医学工程
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再生医学
✓ 已验证
DOI
PubMed
高影响因子
Bioactive Materials
·
2022
·
IF 16.874
Haiwei Liang,Yanxiao Ao,Wenjing Li,Kaini Liang,Baixue Tang,Junyang Li,Jianwei Wang,Xiaoyu Zhu,Yanan Du
Hematopoietic syndrome of acute radiation syndrome (h-ARS) is an acute illness resulted from the damage of bone marrow (BM) microenvironment after exposure to radiation. Currently, the clinical management of h-ARS is limited to medication-assisted treatment, while there is still no specific therapy for the hematopoietic injury from high-dose radiation exposure. Our study aimed to assemble biomimetic three-dimensional (3D) BM microniches by co-culture of hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stem cells (MSCs) in porous, injectable and viscoelastic microscaffolds in vitro . The biodegradable BM microniches were then transplanted in vivo into the BM cavity for the treatment of h-ARS. We demonstrated that the maintenance of HSPCs was prolonged by co-culture with MSCs in the porous 3D microscaffolds with 84 μm in pore diameter and 11.2 kPa in Young's modulus compared with 2D co-culture system. Besides, the minimal effective dose and therapeutic effects of the BM microniches were investigated on a murine model of h-ARS, which showed that the intramedullary cavity-injected BM microniches could adequately promote hematopoietic reconstitution and mitigate death from acute lethal radiation with a dose as low as 1000 HSPCs. Furthermore, the mRNA expression of Notch1 and its downstream target gene Hes1 of HSPCs were increased when co-cultured with MSCs, while the Jagged1 expression of the co-cultured MSCs was upregulated, indicating the significance of Notch signaling pathway in maintenance of HSPCs. Collectively, our findings provide evidence that biomimetic and injectable 3D BM microniches could maintain HSPCs, promote hematopoiesis regeneration and alleviate post-radiation injury, which provides a promising approach to renovate conventional HSPCs transplantation for clinical treatment of blood and immune disorders.
研究领域:
干细胞研究
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再生医学
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辐射生物学
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组织工程
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DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2023
·
IF 5.8
Xingming Wang,Xiupeng Zhu,Danni Wang,Xiaoxu Li,Juan Wang,Guangfu Yin,Zhongbing Huang,Ximing Pu
Inefficient use and loss of exogenously implanted mesenchymal stem cells (MSCs) are major concerns in MSCs-based bone tissue engineering. It is a promising approach to overcome the above issues by recruiting and regulation of endogenous MSCs. However, there are few substances that can recruit MSCs effectively and specifically to the site of bone injury. In this study, we identified a phage clone (termed P11) with specific affinity for MSCs through phage display biopanning, and further investigated the effects of P11 on the cytological behavior of MSCs and macrophages. The results showed that P11 could bind MSCs specifically and promote the proliferation and migration of MSCs. Meanwhile, P11 could polarize macrophages to the M1 phenotype and significantly changed their morphology, which further enhanced the chemotaxis of MSCs. Additionally, RNA-seq results revealed that P11 could promote the secretion of osteogenesis-related markers in MSCs through the TPL2-MEK-ERK signaling pathway. Altogether, P11 has great potential to be used as growth factor alternatives in bone tissue engineering, with the advantages of cheaper and stable activity. Our study also advances the understanding of the effects of phages on macrophages and MSCs, and provides a new idea for the development in the field of phage-based tissue engineering.
研究领域:
组织工程
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干细胞生物学
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骨再生
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噬菌体疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2024
·
IF 9.4
Shixin Xu,Miaomiao Zhang,Ruoying Wang,Jinxin Zhang,Chengwei Wang,Li Xie,Wen Zhao
Secretomes from mesenchymal stem cells (MSCs) have significant therapeutic potential and could be the basis for future MSCs treatments. Innovative design of the topology of biomaterials, which mechanically regulate cell behavior and function, can tremendously improve the efficacy of stem cell therapy. However, how spatial dimension cues derived from specific topology command cell mechanotransduction to regulate the paracrine function of MSCs remains unknown. In this study, the three-dimensional (3D) fibrous constructs with box-like pores and precise strand spacing from 150 μm down to only 40 μm were manufactured using melt electrowriting (MEW), which were used to systematically investigate the spatial dimension cues-triggered mechanotransduction of adipose-derived mesenchymal stem cells (Ad-MSCs) and their impact on the paracrine and regeneration function of Ad-MSCs. The results demonstrated that spatial instructions from the 3D fibrous constructs could influence the spatial reorganization of the cytoskeleton, resulting in cell elongation and augmented immunomodulatory and angiogenic paracrine effects of Ad-MSCs, which was most pronounced at a minimum strand spacing of 40 μm. Besides, mechanical activation of the FAK-PI3K/AKT axis significantly enhanced the paracrine function of Ad-MSCs. In vivo experiments demonstrated that the Ad-MSCs trained using well-defined 3D fibrous constructs with a strand spacing of 40 μm significantly promoted skin regeneration via paracrine signals. In conclusion, this study provides a new horizon for deciphering space dimension insights into the interactional mechanisms of mechanotransduction in regulating cell function, which has inspired innovations in biomaterials for improving tissue regeneration. Statement of Significance Designing cell-scale spatial dimension cues in engineered constructs potentiates the paracrine and regenerative functions of Ad-MSCs. FAK-PI3K/AKT signaling serves as the key mechanotransduction checkpoints for spatial dimension cues triggering mechanical activation. Paracrine signals of Ad-MSCs triggered by mechanical activation promotes skin repair and regeneration via the immunomodulation and angiogenesis.
研究领域:
组织工程
·
干细胞生物学
·
生物材料科学
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力学生物学
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再生医学
✓ 已验证
DOI
PubMed
高影响因子
Cell Stem Cell
·
2026
·
IF 23.3
Shuyue Xu,Jingwen Xu,Qiqi Yang,Ju Zeng,Mengjie Zhang,Yuge Wu,Zhen Liu,Qun Wang,Qing You,Shiyi Zhang
Tumors are increasingly recognized as a consequence of systemic immune dysregulation, while current therapies merely focus on direct tumor killing or local immune activation, overlooking the systemic immune landscape that enables tumorigenesis and metastasis. Targeting distal immune organs, such as the bone marrow (BM), without perturbing tumors remains challenging. Here, we develop a BM-targeted and tumor-evasive cell vector that restricts immunomodulation to the BM niche, enabling systemic immune reprogramming through niche-derived signaling. This mesenchymal stem cell (MSC)-based vector overexpresses Golgi apparatus protein 1 (MSC Glg1 ) to mimic BM affinity signals. In a myelosuppression model, MSC Glg1 delivers CDK4/6 inhibitors (CDK4/6i) to protect hematopoietic stem and progenitor cells (HSPCs) from chemotherapy toxicity while preserving antitumor efficacy. In a subcutaneous tumor model, MSC Glg1 delivers interleukin-7 (IL-7), restoring immune competence without promoting tumor proliferation. This strategy establishes a versatile framework for targeted immunomodulation to treat cancer as a systemic immune disease.
✓ 已验证
DOI
PubMed
高影响因子
Stem Cell Research & Therapy
·
2021
·Vol. 12
·期 1
·1-15
·
IF 6.832
Ma Yinzhong,Wang Lisha,Yang Shilun,Liu Dongyu,Zeng Yi,Lin Lilong,Qiu Linhui,Lu Jiahao,Chang Junlei,Li Zhihuan
Background The therapeutic efficacy of mesenchymal stem cells (MSCs) of different tissue origins on metabolic disorders can be varied in many ways but remains poorly defined. Here we report a comprehensive comparison of human MSCs derived from umbilical cord Wharton’s jelly (UC-MSCs), dental pulp (PU-MSCs), and adipose tissue (AD-MSCs) on the treatment of glucose and lipid metabolic disorders in type II diabetic mice.Methods Fourteen-to-fifteen-week-old male C57BL/6 db/db mice were intravenously administered with human UC-MSCs, PU-MSCs, and AD-MSCs at various doses or vehicle control once every 2 weeks for 6 weeks. Metformin (MET) was given orally to animals in a separate group once a day at weeks 4 to 6 as a positive control. Body weight, blood glucose, and insulin levels were measured every week. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed every 2 weeks. All the animals were sacrificed at week 6 and the blood and liver tissues were collected for biochemical and histological examinations.Results UC-MSCs showed the strongest efficacy in reducing fasting glucose levels, increasing fasting insulin levels, and improving GTT and ITT in a dose-dependent manner, whereas PU-MSCs showed an intermediate efficacy and AD-MSCs showed the least efficacy on these parameters. Moreover, UC-MSCs also reduced the serum low-density lipoprotein cholesterol (LDL-C) levels with the most prominent potency and AD-MSCs had only very weak effect on LDL-C. In contrast, AD-MSCs substantially reduced the lipid content and histological lesion of liver and accompanying biomarkers of liver injury such as serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, whereas UC-MSCs and PU-MSCs displayed no or modest effects on these parameters, respectively.Conclusion sTaken together, our results demonstrated that MSCs of different tissue origins can confer substantially different therapeutic efficacy in ameliorating glucose and lipid metabolic disorders in type II diabetes. MSCs with different therapeutic characteristics could be selected according to the purpose of the treatment in the future clinical practice.
研究领域:
干细胞生物学
·
代谢障碍
·
糖尿病研究
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
Bioactive Materials
·
2022
·
IF 16.874
Min Nie,Bin Kong,Guopu Chen,Ying Xie,Yuanjin Zhao,Lingyun Sun
As a novel cellular therapy, the anti-inflammatory and immunomodulatory virtues of mesenchymal stem cells (MSCs) make them promising candidates for systemic sclerosis (SSc) treatment. However, the clinical efficacy of this stratagem is limited because of the short persistence time, poor survival, and engraftment of MSCs after injection in vivo . Herein, we develop a novel MSCs-laden injectable self-healing hydrogel for SSc treatment. The hydrogel is prepared using N, O-carboxymethyl chitosan (CS-CM) and 4-armed benzaldehyde-terminated polyethylene glycol (PEG-BA) as the main components, imparting with self-healing capacity via the reversible Schiff-base connection between the amino and benzaldehyde groups. We demonstrate that the hydrogel laden with MSCs not only promoted the proliferation of MSCs and increased the cellular half-life in vivo , but also improve their immune-modulating functions. The tube formation assay indicates that the MSCs could significantly promote angiopoiesis. Moreover, the MSCs-laden hydrogel could inhibit fibrosis by modulating the synthesis of collagen and ameliorate disease progression in SSc disease model mice after subcutaneous injection of bleomycin. All these results highlight this novel MSCs-laden hydrogel and its distinctive functions in treatment of chronic SSc, indicating the additional potential to be used widely in the clinic.
研究领域:
干细胞疗法
·
材料科学
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免疫学
·
组织工程
·
药学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）