Regenerative Therapy最新文献_第10页

Targeting ER stress-mediated apoptosis by MSC-derived exosomes: A novel therapeutic strategy against pulmonary fibrosis 骨髓间质干细胞衍生外泌体靶向内质网应激介导的细胞凋亡：一种治疗肺纤维化的新策略

IF 3.5 3区环境科学与生态学 Q3 CELL & TISSUE ENGINEERING

Regenerative Therapy

Pub Date : 2025-10-17 DOI: 10.1016/j.reth.2025.10.004

Ruixi Luo, Yaqiong Wei, La Wang, Peng Chen, Didong Lou, Weiyi Tian

Introduction

Idiopathic pulmonary fibrosis (IPF) is marked by a gradual decline in pulmonary function over time and is associated with a grim prognosis. In the pathogenesis of IPF, persistent endoplasmic reticulum (ER) stress plays a significant role in promoting fibrosis through pathways involving apoptosis. Mesenchymal stem cell-derived exosomes (MSC-Ex) have shown promise in mitigating pulmonary fibrosis by inhibiting apoptosis. Nonetheless, the precise mechanisms underlying this effect remain unclear. In our previous findings, we demonstrated that MSCs alleviate pulmonary fibrosis by regulating ER stress. Building upon this, we sought to investigate whether MSC-Ex could mitigate alveolar epithelial cell apoptosis through the ER stress pathway. We posited that targeting ER stress could represent a crucial mechanism by which MSC-Ex alleviate apoptosis in IPF models.

Methods and results

In this study, bleomycin (BLM) induced apoptosis in A549 cells, and MSC-Ex treatment reduced apoptotic cells and the Bax/Bcl-2 ratio. ER stress is involved in BLM-induced apoptosis in A549 cells, and MSC-Ex reduced ER stress-related protein (Bip and CHOP) expression and reversed the morphological changes of the ER in A549 cells. Moreover, blockade of ER stress with ER stress inhibitor TUDCA contributed to the amelioration of apoptosis in A549 cells, indicating that MSC-Ex reduced BLM-induced apoptosis at least partly by modulating ER stress. In vivo, MSC-Ex injection decreased BLM-induced pulmonary fibrosis in mice, as well as ER stress and apoptosis in the lung tissues.

Conclusions

In conclusion, ER stress induced apoptosis in BLM-treated A549 cells, and MSC-Ex treatment mitigated apoptosis via inhibiting ER stress. This study provides a novel mechanism for MSC-Ex-mediated protection on apoptosis in an IPF model and suggests that MSC-Ex could be a promising therapeutic strategy for IPF.

特发性肺纤维化（IPF）的特点是随着时间的推移肺功能逐渐下降，预后不佳。在IPF的发病机制中，持续内质网（ER）应激通过涉及细胞凋亡的途径在促进纤维化中起重要作用。间充质干细胞来源的外泌体（MSC-Ex）已显示出通过抑制细胞凋亡来减轻肺纤维化的前景。尽管如此，这种效应背后的确切机制仍不清楚。在我们之前的研究中，我们证明了间充质干细胞通过调节内质网应激来减轻肺纤维化。在此基础上，我们试图研究MSC-Ex是否可以通过内质网应激途径减轻肺泡上皮细胞凋亡。我们假设靶向内质网应激可能是MSC-Ex减轻IPF模型中细胞凋亡的关键机制。方法和结果在本研究中，博来霉素（BLM）诱导A549细胞凋亡，MSC-Ex处理可降低凋亡细胞数和Bax/Bcl-2比值。内质网应激参与了blm诱导的A549细胞凋亡，MSC-Ex可降低内质网应激相关蛋白（Bip和CHOP）的表达，逆转A549细胞内质网形态学变化。此外，内质网应激抑制剂TUDCA阻断内质网应激有助于改善A549细胞的凋亡，这表明MSC-Ex至少在一定程度上通过调节内质网应激来减少blm诱导的细胞凋亡。在体内，MSC-Ex注射液可减轻blm诱导的小鼠肺纤维化，减少肺组织内质网应激和细胞凋亡。结论内质网应激可诱导blm处理的A549细胞凋亡，而MSC-Ex可通过抑制内质网应激减轻细胞凋亡。本研究提供了一种新的MSC-Ex在IPF模型中介导细胞凋亡保护的机制，并表明MSC-Ex可能是一种有前景的IPF治疗策略。

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引用次数: 0

Multimodal mechanisms of platelet-rich plasma in bone defect repair: Angiogenesis, inflammation modulation, and metabolic regulation 富血小板血浆在骨缺损修复中的多模式机制：血管生成、炎症调节和代谢调节

IF 3.5 3区环境科学与生态学 Q3 CELL & TISSUE ENGINEERING

Regenerative Therapy

Pub Date : 2025-10-15 DOI: 10.1016/j.reth.2025.09.007

Junjie Chen , Bo Liu , Jiayang He , Yuhao Wei , Yuhan He , Hang Zhou , Zhiqiang Zhang , Yiwen Weng , Ming Cheng

Bone defect is the loss of bone tissue due to trauma, fracture, infection, etc. This loss may lead to non-union of fracture, bone defect or bone deficiency, which seriously affects the patient's quality of life and even leads to dysfunction and disability. Although surgical repair is a common treatment modality, the surgical procedure is complicated, with a long postoperative recovery period and certain surgical risks, such as infection and bleeding. Platelet-rich plasma (PRP), as a novel therapeutic approach, has demonstrated remarkable potential in bone defect repair. PRP is rich in growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), etc., and can have a beneficial effect on bone defect repair through various mechanisms, such as the release of growth factors, the promotion of angiogenesis, the inhibition of inflammatory response, and the recruitment of activated cells and other mechanisms, which play a positive role in the repair of bone defects and provide strong support for the regeneration and repair of bone tissue.

骨缺损是指由于外伤、骨折、感染等导致的骨组织丢失。这种损失可能导致骨折不愈合、骨缺损或骨缺乏，严重影响患者的生活质量，甚至导致功能障碍和残疾。虽然手术修复是常见的治疗方式，但手术过程复杂，术后恢复期长，存在一定的手术风险，如感染、出血等。富血小板血浆（PRP）作为一种新的治疗方法，在骨缺损修复中显示出巨大的潜力。PRP中含有丰富的生长因子，如血小板源性生长因子（PDGF）、转化生长因子-β (TGF-β)、血管内皮生长因子（VEGF）等，可通过多种机制，如释放生长因子、促进血管生成、抑制炎症反应、募集活化细胞等机制，对骨缺损修复产生有益作用。对骨缺损的修复起到积极的作用，为骨组织的再生和修复提供有力的支持。

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引用次数: 0

Corrigendum to ‘Transplantation of chemically induced liver progenitors in Nagase analbuminemic rats under liver regenerative stimulus’ [Regen Ther 30 (2025) 1–8] “在肝脏再生刺激下化学诱导的永酶无血血症大鼠肝祖细胞移植”的更正[Regen Ther 30 (2025) 1-8]

IF 3.5 3区环境科学与生态学 Q3 CELL & TISSUE ENGINEERING

Regenerative Therapy

Pub Date : 2025-10-15 DOI: 10.1016/j.reth.2025.09.013

Masayuki Fukumoto, Akihiko Soyama, Daisuke Miyamoto, Takanobu Hara, Hajime Matsushima, Hajime Imamura, Mampei Yamashita, Tomohiko Adachi, Kengo Kanetaka, Susumu Eguchi

引用次数: 0

Bone morphogenetic protein-2-derived osteogenic peptide promotes bone regeneration via osteoblastogenesis 骨形态发生蛋白-2衍生成骨肽通过成骨细胞形成促进骨再生

IF 3.5 3区环境科学与生态学 Q3 CELL & TISSUE ENGINEERING

Regenerative Therapy

Pub Date : 2025-10-15 DOI: 10.1016/j.reth.2025.09.006

Jong-Bin Lee , Ji-Youn Hong , Hyeeun Shim , Sehee Kim , Dong Won Lee , Bosun Kwon , Jeong-Ho Yun

Introduction

Bone morphogenetic protein (BMP)-2 plays a critical role in stimulating human mesenchymal stromal cells (hMSCs) differentiation, a key process in bone regeneration. However, the clinical application of BMP-2 has been hindered by several adverse effects. This study evaluated the effectiveness of a newly synthesized BMP2-derived osteogenic peptide (OP), which may overcome the limitations of BMP-2 while preserving its osteogenic potential.

Methods

OP5, selected from the OP family based on its osteogenic potential, was tested in vitro to compare its effects on osteogenic signaling, osteoblast differentiation, and hMSC gene expression in with those of BMP-2. New bone formation stimulated by OP5 or BMP-2 was assessed in vivo using radiographic and histological analyses in a rat model of calvarial defects.

Results

The optimal OP5 concentration of 1 μM supported hMSC viability and exhibited potent osteogenic activity. OP5 significantly activated BMP receptor types IA and II binding and the osteogenic protein kinase A and phosphorylated cAMP response element-binding protein signaling pathway. OP5-induced gene expressions of alkaline phosphatase and osteocalcin peaked on day 4 (early osteogenesis) and were sustained until day 14 (late osteogenesis). In vivo, 100 μg OP5 demonstrated superior bone formation compared to other doses (50, 300, and 600 μg), but was less effective than BMP-2. The amount of bone regeneration varied with different doses of OP5.

Conclusions

OP5, a low-molecular-weight peptide with strong osteogenic potential, may be a viable alternative to BMP-2 for clinical bone regeneration, minimizing BMP2-associated adverse effects.

骨形态发生蛋白(BMP)-2在刺激人间充质间质细胞（hMSCs）分化中起关键作用，这是骨再生的关键过程。然而，BMP-2的临床应用一直受到一些不良反应的阻碍。本研究评估了新合成的BMP-2衍生成骨肽（OP）的有效性，该肽可能克服BMP-2的局限性，同时保留其成骨潜能。方法从OP家族中选择具有成骨潜能的sop5进行体外检测，比较其与BMP-2对成骨信号传导、成骨细胞分化和hMSC基因表达的影响。在大鼠颅骨缺损模型中，通过x线摄影和组织学分析评估OP5或BMP-2刺激的新骨形成。结果1 μM的最佳OP5浓度支持hMSC的存活，并表现出较强的成骨活性。OP5显著激活BMP受体IA型和II型结合以及成骨蛋白激酶A和磷酸化cAMP反应元件结合蛋白信号通路。op5诱导的碱性磷酸酶和骨钙素基因表达在第4天（早期成骨）达到峰值，并持续到第14天（晚期成骨）。在体内，与其他剂量（50、300和600 μg）相比，100 μg的OP5表现出更好的骨形成，但效果不如BMP-2。不同剂量OP5对骨再生的影响不同。结论sop5是一种具有较强成骨潜能的低分子量肽，可作为BMP-2的替代品用于临床骨再生，减少BMP-2相关的不良反应。

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引用次数: 0

Assessment of permeability in deep tissue capillaries using a new method reflects the nutrient supply status in a healthy heart 用一种新的方法评估深层组织毛细血管的通透性，反映了健康心脏的营养供应状况

IF 3.5 3区环境科学与生态学 Q3 CELL & TISSUE ENGINEERING

Regenerative Therapy

Pub Date : 2025-10-14 DOI: 10.1016/j.reth.2025.10.005

Mio Nakamura , Yurika Yoshida-Kikkawa , Kousuke Sugiura , Yoko Itakura , Kensuke Ohse , Norihiko Sasaki , Yuzuru Ito , Masashi Toyoda

Introduction

The in vitro organoid model is a valuable tool for studying organ development and disease. However, a key current challenge is the absence of a functional vascular compartment, which results from limited understanding of capillary function in vivo. Multisystem disorders involve physiological abnormalities that affect different organs in various ways. Notably, women have a higher prevalence of microvessel disease in the heart compared to men. This is because, until now, there has been no way to detect or evaluate the material exchange functions carried out by capillaries deep within healthy heart tissue.

Methods

To detect fluorescent material leaking from intracardiac microvessels deep within the left ventricular wall under healthy conditions, female mice were injected with fluorescent dextran via the tail vein. The heart tissue was quickly removed, frozen, sliced, and examined directly under fluorescence. Additionally, the extent of the fluorescent substance diffusion was measured in young and aged female mice.

Results

We observed fluorescent substances leaking from deep heart capillaries under healthy conditions. We then developed a method to measure capillary permeability by assessing the diffusion area. Furthermore, this method showed that the permeability of capillaries in the hearts of aged female mice was lower than that of young female mice.

Conclusion

We have developed a method to assess capillary permeability in deep tissue. This research will improve our understanding of how capillaries exchange substances and support tissue function. This new method will not only provide new insights into studies of cardiac disease risk and sex differences, but also assist in developing more advanced in vitro models. It will further aid in refining the best cell transplantation techniques.

体外类器官模型是研究器官发育和疾病的重要工具。然而，目前的一个关键挑战是缺乏功能性血管室，这是由于对体内毛细血管功能的了解有限造成的。多系统疾病包括以各种方式影响不同器官的生理异常。值得注意的是，与男性相比，女性心脏微血管疾病的患病率更高。这是因为，到目前为止，还没有办法检测或评估健康心脏组织深处毛细血管所执行的物质交换功能。方法在健康状态下，雌性小鼠经尾静脉注射荧光葡聚糖，检测左室壁深处心内微血管渗漏的荧光物质。迅速取出心脏组织，冷冻，切片，并在荧光下直接检查。此外，还测量了荧光物质在年轻和老年雌性小鼠中的扩散程度。结果在健康状态下，心脏深层毛细血管有荧光物质渗漏。然后，我们开发了一种通过评估扩散面积来测量毛细管渗透率的方法。此外，该方法还显示老年雌性小鼠心脏毛细血管通透性低于年轻雌性小鼠。结论建立了一种评价深部组织毛细血管通透性的方法。这项研究将提高我们对毛细血管交换物质和支持组织功能的理解。这种新方法不仅将为心脏病风险和性别差异的研究提供新的见解，而且还有助于开发更先进的体外模型。这将进一步帮助完善最好的细胞移植技术。

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引用次数: 0

Functionalization of 3D printed PLGA-based scaffolds for bone regeneration 基于plga的3D打印骨再生支架功能化研究

IF 3.5 3区环境科学与生态学 Q3 CELL & TISSUE ENGINEERING

Regenerative Therapy

Pub Date : 2025-10-13 DOI: 10.1016/j.reth.2025.10.003

Xuan Yan , Yanhua Wei , Yicai Luo , Ziwei Wu , Zhe Liu , Hongbing Liao

Bone defect remains an intractable issue for clinical orthopedics owing to their varied sizes and irregular shapes. Poly (lactic acid-co-glycolic acid) (PLGA)-based artificial bone grafts has garnered considerable attention in bone repair owing to their outstanding biocompatibility and tunable biodegradability. 3D printing technology is a feasible means due to its ability to construct scaffolds with defined shapes for restoring bone defects in clinical practice. In this review, the physicochemical properties of PLGA and 3D printing technology are briefly introduced. In addition, diverse strategies to improve the osteogenic performance of 3D printed PLGA scaffolds are elaborated. Finally, current challenges and future perspectives of 3D printed PLGA scaffolds applied in clinical practice are proposed.

骨缺损由于其大小不一、形状不规则，一直是骨科临床的难题。聚乳酸-羟基乙酸（PLGA）为基础的人工骨由于其优异的生物相容性和可调节的生物降解性在骨修复中引起了广泛的关注。3D打印技术能够构建具有特定形状的支架用于骨缺损修复，在临床实践中是一种可行的手段。本文简要介绍了PLGA的理化性质和3D打印技术。此外，还阐述了提高3D打印PLGA支架成骨性能的多种策略。最后，提出了3D打印PLGA支架在临床应用中面临的挑战和未来的展望。

引用次数: 0

Primed human pluripotent stem cell-derived blastocyst-like cell aggregates with partial lineage specification 引物人类多能干细胞衍生的囊胚样细胞聚集体与部分谱系规范

IF 3.5 3区环境科学与生态学 Q3 CELL & TISSUE ENGINEERING

Regenerative Therapy

Pub Date : 2025-10-13 DOI: 10.1016/j.reth.2025.10.007

Kaori Mutsuda-Zapater , Xiaopeng Wen , Satoshi Imamura , Shiho Terada , Kyoko Sawada , Kei Saito , Ken-ichiro Kamei

Introduction

Human blastoids, blastocyst-like structures assembled in vitro, hold great promise for decoding the earliest steps of human development. However, most existing protocols rely on naïve human pluripotent stem cells (hPSCs), which are chromosomally unstable and technically demanding.

Methods

We developed a method to generate human blastocyst-like cell aggregates directly from primed hPSCs using a thermoresponsive hydrogel. Generated blastocyst-like cell aggregates were evaluated for morphological features, lineage marker expression via immunocytochemistry, transcriptional profiles using single-cell RNA sequencing, and functional capacity through in vitro implantation assays.

Results

Primed hPSC-derived blastocyst-like cell aggregates recapitulated key morphological features of human blastocysts, including cyst formation and spatial expression of epiblast, trophectoderm, and primitive endoderm markers. Single-cell RNA sequencing revealed that a subset of cells showed transcriptional profiles resembling epiblast-, trophectoderm-, and primitive endoderm-like cells although a substantial proportion remained undifferentiated. Functionally, blastocyst-like cell aggregates demonstrated in vitro implantation potential, trophoblast differentiation, and secretion of human chorionic gonadotropin.

Conclusions

This work introduces a more accessible platform for generating human blastocyst-like cell aggregates from primed hPSCs, broadening their utility for investigating early development events. Insights gained from blastocyst-like cell aggregates have the potential to advance the modelling of early-onset diseases, drive innovations in regenerative therapies, and contribute to the development of assisted reproductive technologies.

人类胚泡，即体外组装的囊胚样结构，在解码人类发育的最初阶段方面有着巨大的希望。然而，大多数现有的方案依赖于naïve人类多能干细胞（hPSCs），这是染色体不稳定和技术要求高。方法建立了一种利用热反应性水凝胶直接从引物的hPSCs中生成人囊胚样细胞聚集体的方法。通过免疫细胞化学评估生成的囊胚样细胞聚集体的形态特征、谱系标记表达、单细胞RNA测序的转录谱和体外植入试验的功能能力。结果衍生的胚泡样细胞聚集体重现了人胚泡的主要形态学特征，包括囊的形成和外胚层、滋养外胚层和原始内胚层标记物的空间表达。单细胞RNA测序显示，一部分细胞表现出类似外胚层、滋养外胚层和原始内胚层样细胞的转录谱，尽管很大一部分细胞仍未分化。在功能上，囊胚样细胞聚集体表现出体外植入潜力、滋养细胞分化和人绒毛膜促性腺激素的分泌。本研究为从引物的人造血干细胞中生成人囊胚样细胞聚集体提供了一个更容易获得的平台，扩大了其在研究早期发育事件中的应用范围。从囊胚样细胞聚集体中获得的见解有可能推进早发性疾病的建模，推动再生疗法的创新，并有助于辅助生殖技术的发展。

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引用次数: 0

Dose-response immunomodulatory effects of Mesenchymal stem cell-derived culture-conditioned media in acute Graft-versus-Host Disease 间充质干细胞衍生培养条件培养基在急性移植物抗宿主病中的剂量-反应免疫调节作用

IF 3.5 3区环境科学与生态学 Q3 CELL & TISSUE ENGINEERING

Regenerative Therapy

Pub Date : 2025-10-08 DOI: 10.1016/j.reth.2025.10.001

Mohini Mendiratta , Meenakshi Mendiratta , Sujata Mohanty , Sandeep Rai , Ritu Gupta , Vatsla Dadhwal , Sameer Bakhshi , Deepam Pushpam , Mukul Aggarwal , Aditya Kumar Gupta , Ranjit Kumar Sahoo

Background

Mesenchymal stem cell-based therapy faces challenges that have driven interest in MSCs-derived culture-conditioned media (CCM) as a cell-free alternative. Our study aims to optimize the dose and collection timing of CCM to enhance its therapeutic efficacy in aGVHD, while also standardizing co-culture conditions for CD3⁺ T-cell interaction with CCM.

Material and methods

Human MSCs were isolated from BM and WJ and subsequently preconditioned under hypoxic conditions (1 % O₂) for 24 h in a tri-gas incubator. Culture-conditioned media (CCM) were collected from both naive (MSCs) and hypoxia-preconditioned MSCs (MSCs^HYP) at 24, 48, and 72 h and filtered using a 0.2 μm membrane filter. CD3⁺ T-cell were isolated from PBMNCs derived from aGVHD patients. These T-cell were co-cultured at varying densities (2∗10⁶, 5∗10⁶, and 10∗10⁶ cells/ml) with different concentrations of CCM (25 %, 50 %, and 100 %), and cell proliferation was assessed using the MTS assay. Furthermore, CD3⁺ T-cell proliferation and activation status were evaluated in a 2D co-culture model of CD3⁺ T-cell and CCM using flow cytometry.

Results

Our findings revealed that CCM collected at 48 h, at a 50 % concentration, exerted the most pronounced inhibitory effect on CD3⁺ T-cell proliferation, particularly at a density of 5∗10⁶ cells/ml, irrespective of the MSCs source. Hypoxia preconditioning significantly enhanced the immunomodulatory effects, with WJ-MSCs^HYP-CCM demonstrating superior efficacy in suppressing T-cell proliferation, increasing the CD4⁺/CD8⁺ T-cell ratio, and reducing CD4⁺ T-cell activation compared to BM-MSCs^HYP-CCM.

Conclusion

These results emphasize the critical role of optimizing CCM collection timing and concentration to maximize therapeutic potential. Our study paves the way for the development of standardized, scalable, and effective cell-free therapies for aGVHD.

基于间充质干细胞的治疗面临着挑战，人们对间充质干细胞衍生的培养条件培养基（CCM）作为一种无细胞替代疗法产生了兴趣。我们的研究旨在优化CCM的剂量和采集时间，以提高其对aGVHD的治疗效果，同时规范CCM与CD3+ t细胞相互作用的共培养条件。材料和方法从BM和WJ中分离出人间充质干细胞，随后在三气培养箱中缺氧条件（1% O2）预处理24小时。培养条件培养基（CCM）分别于24、48和72 h从未处理（MSCs）和缺氧预处理的MSCs （MSCsHYP）中收集，并使用0.2 μm膜过滤器过滤。从aGVHD患者的pbmnc中分离CD3+ t细胞。这些t细胞以不同密度（2∗106,5∗106和10∗106细胞/ml）与不同浓度的CCM（25%， 50%和100%）共培养，并使用MTS法评估细胞增殖。此外，在CD3+ t细胞和CCM的二维共培养模型中，使用流式细胞术评估CD3+ t细胞的增殖和激活状态。我们的研究结果显示，无论MSCs来源如何，在48小时收集的CCM以50%的浓度对CD3+ t细胞增殖具有最明显的抑制作用，特别是当密度为5∗106个细胞/ml时。低氧预处理显著增强免疫调节作用，WJ-MSCsHYP-CCM在抑制t细胞增殖、提高CD4+/CD8+ t细胞比例、降低CD4+ t细胞活化方面优于BM-MSCsHYP-CCM。结论优化CCM的采集时机和浓度对发挥治疗潜力至关重要。我们的研究为开发标准化、可扩展和有效的aGVHD无细胞疗法铺平了道路。

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引用次数: 0

Modeling epithelial wound closure dynamics with AI: A comparative study across cell types 用人工智能模拟上皮伤口愈合动力学：跨细胞类型的比较研究

IF 3.5 3区环境科学与生态学 Q3 CELL & TISSUE ENGINEERING

Regenerative Therapy

Pub Date : 2025-10-04 DOI: 10.1016/j.reth.2025.10.002

Xueyao Cai , Weidong Li , Wenjun Shi , Yuchen Cai , Jianda Zhou

Background

Skin wound healing exhibits complex spatiotemporal heterogeneity that challenges traditional static assessment methods. Current artificial intelligence (AI) approaches often treat segmentation and temporal modeling as disconnected processes, limiting dynamic quantification of healing trajectories across distinct cell types. We aim to develop an integrated AI framework combining enhanced segmentation with temporal modeling for quantifying in vitro wound closure dynamics in normal epithelial (MCF10A) and tumor (MCF7) cells, and to compare algorithmic performance across healing phenotypes.

Methods

We implemented an enhanced UNet++ model for wound segmentation in time-lapse images, benchmarked against Otsu thresholding. Temporal closure trajectories were modeled using polynomial regression, Random Forest (RF), Support Vector Regression (SVR), Autoregressive Integrated Moving Average (ARIMA), and Temporal Convolutional Network (TCN). Performance was evaluated via Dice/IoU (segmentation) and MAE/R² (temporal modeling).

Results

UNet++ achieved significantly higher segmentation accuracy than Otsu thresholding (Dice: p = 8.841 × 10⁻⁴⁹; IoU: p = 3.931 × 10⁻⁴⁷) with consistent temporal robustness across healing phases. For closure trajectory modeling, RF achieved superior accuracy for MCF7 (mean absolute error [MAE] = 0.48 %, R² = 0.968) and MCF10A (MAE = 1.73 %, R² = 0.872), excelling in capturing nonlinear phase transitions and plateau behaviors. TCN showed promise for abrupt changes in MCF7 (MAE = 1.67 %, R² = 0.698) but failed for near-stationary MCF10A trends. Significant cell-type differences emerged, with RF providing the most interpretable predictions.

Conclusion

This integrated framework enables precise dynamic wound monitoring, holding clinical potential for chronic ulcer management and tumor margin surveillance, particularly through its ability to discern cell-type-specific healing phenotypes.

皮肤伤口愈合表现出复杂的时空异质性，这对传统的静态评估方法提出了挑战。目前的人工智能（AI）方法通常将分割和时间建模视为断开的过程，限制了不同细胞类型愈合轨迹的动态量化。我们的目标是开发一个集成的AI框架，将增强分割与时间建模相结合，用于定量正常上皮细胞（MCF10A）和肿瘤细胞（MCF7）的体外伤口愈合动力学，并比较不同愈合表型的算法性能。方法采用基于Otsu阈值的改进UNet++模型对延时图像进行伤口分割。时间闭合轨迹采用多项式回归、随机森林（RF）、支持向量回归（SVR）、自回归综合移动平均（ARIMA）和时间卷积网络（TCN）建模。通过Dice/IoU（分割）和MAE/R2（时间建模）评估性能。结果与Otsu阈值法（Dice: p = 8.841 × 10−49;IoU: p = 3.931 × 10−47）相比，tsunet+ +的分割准确率显著提高，且在各愈合阶段具有一致的时间稳健性。对于闭合轨迹建模，RF对MCF7（平均绝对误差[MAE] = 0.48%, R2 = 0.968）和MCF10A （MAE = 1.73%, R2 = 0.872）具有较高的精度，在捕获非线性相变和平台行为方面表现出色。TCN显示MCF7突变（MAE = 1.67%, R2 = 0.698），但MCF10A接近平稳趋势失败。出现了显著的细胞类型差异，RF提供了最可解释的预测。结论：该集成框架能够实现精确的动态伤口监测，具有慢性溃疡管理和肿瘤边缘监测的临床潜力，特别是通过其识别细胞类型特异性愈合表型的能力。

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引用次数: 0

No simple way to averaging out: Pooled mesenchymal stromal cells do not reflect average donor characteristics 没有简单的平均方法：汇集的间充质间质细胞不能反映供体的平均特征

IF 3.5 3区环境科学与生态学 Q3 CELL & TISSUE ENGINEERING

Regenerative Therapy

Pub Date : 2025-10-03 DOI: 10.1016/j.reth.2025.09.012

Dea Kukaj , Sabine Niebert , Christoph Biehl , Ursula Reichart , Christiane Schueler , Janina Burk

Background

Mesenchymal stromal cells (MSCs) are promising candidates for numerous regenerative therapies. Still, clinical translation is complicated by the heterogeneity of MSCs and related shortcomings in preclinical research. Pooling MSCs from multiple donors is increasingly being advocated as an effective way to mitigate donor variability. However, it remains unclear whether the range of individual cell characteristics is equally reflected in pooled cultures, or if pooling rather leads to a homogenized cell population dominated by the fittest donor, which would lead to skewed results. This study investigates whether MSC pools are functionally representative for their respective donor MSCs and whether dominant donors emerge over time.

Methods

MSCs from nine human donors were categorized into low-, middle-, and high-fitness groups. Individual MSCs were then pooled according to their fitness groups, complemented by a mixed-fitness pool. Functional assays for proliferation, metabolic activity, differentiation, migration and senescence were performed to evaluate the pools versus the individual MSCs. Donor representation within pools was tracked using fluorescence microscopy and qPCR.

Results

The high-fitness pool, as well as its individual donor MSCs, displayed the most rapid proliferation and highest metabolic activity. However, while for proliferation, the pool data aligned well with the individual donor data, all other assays revealed discrepancies between the pooled cultures and individual donor cells. Interestingly, particularly the mixed fitness pool showed inferior metabolic activity and differentiation potential in comparison with the respective individual donor MSCs. Cell tracking showed that over one passage, even pools composed of donors with similar cell fitness became dominated by the donor with the highest cellular fitness.

Conclusions

The discrepancy between pooled and individual donor data emphasizes the importance of biological replicates to capture donor variation and ensure that MSC research reflects natural diversity.

间充质基质细胞（MSCs）是许多再生治疗的有希望的候选者。然而，由于间充质干细胞的异质性和临床前研究的相关缺陷，临床翻译变得复杂。越来越多的人提倡将来自多个供体的间充质干细胞集中起来，作为减少供体多样性的有效方法。然而，目前尚不清楚单个细胞特征的范围是否在混合培养中得到了同样的反映，或者混合培养是否导致了由最适合的供体主导的均匀细胞群，这将导致结果偏差。这项研究调查了MSC池是否在功能上代表了各自的供体MSC，以及是否随着时间的推移出现了主导供体。方法将9例人类供体的smscs分为低、中、高适应度组。然后根据其健身组对单个msc进行汇总，并辅以混合健身池。进行增殖、代谢活性、分化、迁移和衰老的功能分析，以评估池与单个MSCs的差异。使用荧光显微镜和qPCR追踪供体在池中的代表性。结果高适能池及其供体间充质干细胞增殖最快，代谢活性最高。然而，尽管对于增殖，池数据与个体供体数据很好地一致，但所有其他检测显示池培养和个体供体细胞之间存在差异。有趣的是，特别是混合健身池与各自的单个供体间充质干细胞相比，显示出较差的代谢活性和分化潜力。细胞追踪显示，经过一次传代，即使是由细胞适应度相似的供体组成的供体池也会被细胞适应度最高的供体所支配。结论集合供体和个体供体数据之间的差异强调了生物复制对捕获供体变异和确保MSC研究反映自然多样性的重要性。

{"title":"No simple way to averaging out: Pooled mesenchymal stromal cells do not reflect average donor characteristics","authors":"Dea Kukaj , Sabine Niebert , Christoph Biehl , Ursula Reichart , Christiane Schueler , Janina Burk","doi":"10.1016/j.reth.2025.09.012","DOIUrl":"10.1016/j.reth.2025.09.012","url":null,"abstract":"<div><h3>Background</h3><div>Mesenchymal stromal cells (MSCs) are promising candidates for numerous regenerative therapies. Still, clinical translation is complicated by the heterogeneity of MSCs and related shortcomings in preclinical research. Pooling MSCs from multiple donors is increasingly being advocated as an effective way to mitigate donor variability. However, it remains unclear whether the range of individual cell characteristics is equally reflected in pooled cultures, or if pooling rather leads to a homogenized cell population dominated by the fittest donor, which would lead to skewed results. This study investigates whether MSC pools are functionally representative for their respective donor MSCs and whether dominant donors emerge over time.</div></div><div><h3>Methods</h3><div>MSCs from nine human donors were categorized into low-, middle-, and high-fitness groups. Individual MSCs were then pooled according to their fitness groups, complemented by a mixed-fitness pool. Functional assays for proliferation, metabolic activity, differentiation, migration and senescence were performed to evaluate the pools versus the individual MSCs. Donor representation within pools was tracked using fluorescence microscopy and qPCR.</div></div><div><h3>Results</h3><div>The high-fitness pool, as well as its individual donor MSCs, displayed the most rapid proliferation and highest metabolic activity. However, while for proliferation, the pool data aligned well with the individual donor data, all other assays revealed discrepancies between the pooled cultures and individual donor cells. Interestingly, particularly the mixed fitness pool showed inferior metabolic activity and differentiation potential in comparison with the respective individual donor MSCs. Cell tracking showed that over one passage, even pools composed of donors with similar cell fitness became dominated by the donor with the highest cellular fitness.</div></div><div><h3>Conclusions</h3><div>The discrepancy between pooled and individual donor data emphasizes the importance of biological replicates to capture donor variation and ensure that MSC research reflects natural diversity.</div></div>","PeriodicalId":20895,"journal":{"name":"Regenerative Therapy","volume":"30 ","pages":"Pages 849-859"},"PeriodicalIF":3.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145219332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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