药学学报

Physical factor	Regulation mechanism	Application
Mechanical factors	Integrin-FAK/Rho/ROCK/ERK-MAPK pathways^{[23, 24, 27]}; PIEZO1^{[26, 28]}; YAP/TAZ nuclear localization regulation^{[15, 20, 27]}	Bone regeneration, cartilage repair, angiogenesis^{[26, 29]}
Electromagnetic field	Low-frequency EMF activates Wnt/β-catenin pathway; high-frequency EMF activates Erk1/2 pathway^[31-33]; ROS metabolic regulation^[32-35]	Bone defect repair, neural regeneration, spinal cord injury^{[35, 39, 40]}
Photobiomodulation	PI3K/Akt/mTOR pathway & Ca²⁺/ROS signaling^{[43, 44]}; mitochondrial function modulation^[44-48]	Tissue repair, neural regeneration, medical aesthetics^[48-51]
Multifactorial synergy	Combinatorial strategies: mechanics+light, EMF+light, mechanics+EMF^{[32, 43, 45]}	Complex tissue repair^{[35, 40]}

Physical factor

Regulation mechanism

Application

Mechanical factors

Integrin-FAK/Rho/ROCK/ERK-MAPK pathways^{[23, 24, 27]}; PIEZO1^{[26, 28]}; YAP/TAZ nuclear localization regulation^{[15, 20, 27]}

Bone regeneration, cartilage repair, angiogenesis^{[26, 29]}

Electromagnetic field

Low-frequency EMF activates Wnt/β-catenin pathway; high-frequency EMF activates Erk1/2 pathway^[31-33]; ROS metabolic regulation^[32-35]

Bone defect repair, neural regeneration, spinal cord injury^{[35, 39, 40]}

Photobiomodulation

PI3K/Akt/mTOR pathway & Ca²⁺/ROS signaling^{[43, 44]}; mitochondrial function modulation^[44-48]

Tissue repair, neural regeneration, medical aesthetics^[48-51]

Multifactorial synergy

Combinatorial strategies: mechanics+light, EMF+light, mechanics+EMF^{[32, 43, 45]}

Complex tissue repair^{[35, 40]}

Physical factor	Regulation mechanism	Application
Mechanical factors	Integrin-FAK/Rho/ROCK/ERK-MAPK pathways^{[23, 24, 27]}; PIEZO1^{[26, 28]}; YAP/TAZ nuclear localization regulation^{[15, 20, 27]}	Bone regeneration, cartilage repair, angiogenesis^{[26, 29]}
Electromagnetic field	Low-frequency EMF activates Wnt/β-catenin pathway; high-frequency EMF activates Erk1/2 pathway^[31-33]; ROS metabolic regulation^[32-35]	Bone defect repair, neural regeneration, spinal cord injury^{[35, 39, 40]}
Photobiomodulation	PI3K/Akt/mTOR pathway & Ca²⁺/ROS signaling^{[43, 44]}; mitochondrial function modulation^[44-48]	Tissue repair, neural regeneration, medical aesthetics^[48-51]
Multifactorial synergy	Combinatorial strategies: mechanics+light, EMF+light, mechanics+EMF^{[32, 43, 45]}	Complex tissue repair^{[35, 40]}

Physical factor

Regulation mechanism

Application

Mechanical factors

Integrin-FAK/Rho/ROCK/ERK-MAPK pathways^{[23, 24, 27]}; PIEZO1^{[26, 28]}; YAP/TAZ nuclear localization regulation^{[15, 20, 27]}

Bone regeneration, cartilage repair, angiogenesis^{[26, 29]}

Electromagnetic field

Low-frequency EMF activates Wnt/β-catenin pathway; high-frequency EMF activates Erk1/2 pathway^[31-33]; ROS metabolic regulation^[32-35]

Bone defect repair, neural regeneration, spinal cord injury^{[35, 39, 40]}

Photobiomodulation

PI3K/Akt/mTOR pathway & Ca²⁺/ROS signaling^{[43, 44]}; mitochondrial function modulation^[44-48]

Tissue repair, neural regeneration, medical aesthetics^[48-51]

Multifactorial synergy

Combinatorial strategies: mechanics+light, EMF+light, mechanics+EMF^{[32, 43, 45]}

Complex tissue repair^{[35, 40]}

人干细胞物理微环境调控机制研究进展

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姚明鑫 , 谢国玉 , 贾博文 , 刘小萌 , 杨隽 ^*

药学学报 | 综述 2025,60(6): 1582-1588

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药学学报 |综述 2025 , 60 (6) : 1582 -1588

人干细胞物理微环境调控机制研究进展

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姚明鑫, 谢国玉, 贾博文, 刘小萌, 杨隽^*

作者信息

浙江大学医学院, 浙江杭州 310058

通讯作者:

杨隽, E-mail: yang_jun@zju.edu.cn

作者简介:

作者贡献:

姚明鑫具体完成文章撰写; 贾博文负责文献收集; 谢国玉和刘小萌对文章内容进行补充核对; 杨隽负责全程指导和修改审校。

Research advances in the regulatory mechanisms of physical microenvironment on human stem cells

Ming-xin YAO, Guo-yu XIE, Bo-wen JIA, Xiao-meng LIU, Jun YANG^*

Affiliations

Zhejiang University School of Medicine, Hangzhou 310058, China

出版时间: 2025-06-12 doi: 10.16438/j.0513-4870.2025-0060

文章导航

摘要

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干细胞(stem cells, SCs) 是一类具有自我更新能力的细胞, 能够分化成多种人体细胞类型。干细胞再生医学日益兴盛, 国内上市首款干细胞药物——艾米迈托赛注射液, 为患者带来新的希望。目前, 关于干细胞作用的研究多以生物和化学因素为主, 然而物理作用因素的调控具有无创性、时空可控制性等优势。本文就物理因素对干细胞行为调控的机制进行探讨。动态的机械力可通过调控细胞中关键的信号途径如TGFβ/Smad、RAS/MAPK、JAK/STAT途径对干细胞分化及功能进行影响, 这些重要途径的激活对于机体的发育以及相应疾病的发生具有重要意义; 电磁场通过调控细胞膜电位、离子通道的活性及相应的基因表达调控干细胞的增殖、迁移和细胞外基质构建等, 对干细胞的研究开辟新的方向。光生物调节通过改变光参数(波长、强度或时间) 或使用光敏材料调控干细胞, 如光照在调控神经干细胞和骨髓间充质干细胞的研究中发挥重要的作用。多种物理作用因素的协同治疗策略结合3D打印及纳米材料等新的科学与技术手段将进一步促进干细胞研究的发展与应用。

关键词

人体干细胞 / 物理因素 / 细胞机械力 / 电磁场 / 光生物调控

Abstract

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Stem cells (SCs) are a class of self-renewing cells capable of differentiating into various human cell types. The field of stem cell regenerative medicine is flourishing, with China's first approved stem cell drug—Amimestrocel—bringing new hope to patients. Current research on stem cell mechanisms primarily focuses on biological and chemical factors; however, physical regulatory factors (e.g., mechanical forces, electromagnetic fields) offer distinct advantages, including non-invasiveness and temporally precise control. This review explores mechanisms by which physical factors regulate stem cell behavior. Dynamic mechanical forces influence stem cell differentiation and function by modulating key signaling pathways such as TGFβ/Smad, RAS/MAPK, and JAK/STAT, the activation of which plays crucial roles in organismal development and disease pathogenesis. Electromagnetic fields regulate stem cell proliferation, migration, and extracellular matrix remodeling through the modulation of membrane potential, ion channel activity, and gene expression, opening new research directions. Photobiomodulation enables stem cell regulation through adjustments to light parameters (wavelength, intensity, duration) or photosensitive materials, demonstrating significant effects in studies involving neural stem cells and bone marrow mesenchymal stem cells. Synergistic therapeutic strategies combining multiple physical factors with emerging technologies such as 3D printing and nanomaterials will further advance stem cell research and clinical applications.

Key words

human stem cell / physical factor / cell mechanical force / electromagnetic field / photobiomodulation

引用本文

姚明鑫, 谢国玉, 贾博文, 刘小萌, 杨隽. 人干细胞物理微环境调控机制研究进展. 药学学报, 2025 , 60 (6) : 1582 -1588 . DOI: 10.16438/j.0513-4870.2025-0060

Ming-xin YAO, Guo-yu XIE, Bo-wen JIA, Xiao-meng LIU, Jun YANG. Research advances in the regulatory mechanisms of physical microenvironment on human stem cells[J]. Acta Pharmaceutica Sinica, 2025 , 60 (6) : 1582 -1588 . DOI: 10.16438/j.0513-4870.2025-0060

正文

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干细胞是一类具有自我更新能力和多向分化潜能的特异性细胞群体, 在复杂的理化因素影响下, 可以特异性地向神经细胞、心肌细胞、骨细胞等特定功能细胞进行定向分化; 其动态平衡是维持机体组织稳态和受损后修复的基础; 动态平衡的失调被认为与退行性疾病、血液系统疾病等病理过程密切相关^[1-4]。根据发育阶段和分化潜能的不同, 干细胞可分为两大类: 多能干细胞(胚胎干细胞、诱导多能干细胞) 和成体干细胞(间充质干细胞、神经干细胞、造血干细胞等)。其中, 多能干细胞具有分化为机体所有细胞类型的全能性, 而成体干细胞则表现出组织特异性, 能够定向分化为特定谱系的细胞, 在相应组织的再生修复中发挥重要作用。间充质干细胞(mesenchymal stem cells, MSCs) 作为造血微环境的重要组成, 具有抑制免疫反应和促血管生成能力, 广泛应用于组织工程学、免疫系统治疗。造血干细胞因为具有血液细胞分化潜能, 是目前治疗白血病、再生障碍贫血等血液系统疾病不可或缺的治疗手段。干细胞主要通过分化替代损伤细胞, 并通过分泌外泌体或细胞因子作用于体内, 实现组织损伤后结构性修复和功能性的重建。因此, 动态平衡的调控是干细胞与周围组织间复杂网络相互作用的重要基础。我国获批上市的第一个干细胞新药“艾米迈托赛注射液”的有效组分为人脐带MSCs来源的外泌体。该药物的成功上市不仅填补我国干细胞治疗产品的空白, 更标志着我国在干细胞治疗领域实现从基础研究到临床转化的重大突破, 为后续干细胞药物的研发建立重要的技术标准。

干细胞的生理功能、增殖与分化是由遗传信息、生物化学信号及物理信号共同调控的复杂过程^[4-6]。目前, 大部分研究着重于生物化学因素; 其优势在于明确的作用机制和成熟的技术体系, 但该研究方向的局限性日益凸显, 主要体现在单一化学因子的过度干预易引发异常分化、动态调控难以掌控和微环境还原度低。随着对物理因素的认识逐渐深入, 越来越多的研究表明其对干细胞增殖、迁移和分化十分关键。通过模拟天然组织特有的力学微环境, 减少体外培养与体内生理系统间的差异^{[7, 8]}。同时, 物理调控可减少外源性生长因子依赖、降低致瘤风险, 并实现多参数协同效应^{[9, 10]}。由于物理因素在干细胞微环境中起着举足轻重的作用, 因此本文综述近年来力学刺激、电磁场调控、光生物调控等物理手段对干细胞增殖、迁移、分化等的影响及最新研究进展。着重讨论物理因素的调控机制, 探讨多因素协同效应, 评估新兴技术的应用潜力。同时, 针对现有技术瓶颈提出解决方案, 展望其在再生医学领域的转化路径, 并为临床转化提供理论支持。

1　干细胞微环境及其物理因子的关键作用

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干细胞微环境(stem cell niche) 是干细胞自我更新、多向分化及维持相对稳定的局部环境^{[2, 3, 11]}, 受多种化学、生物和物理因素作用协同调控^{[1, 10, 12, 13]}。许多研究表明转化生长因子β (transforming growth factor β, TGFβ)、血管内皮生长因子等生长因子通过Smad、有丝分裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK) 等信号途径调节干细胞生长, 白细胞介素-6 (interleukin-6, IL-6)、肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α) 等炎症因子通过JAK/STAT信号途径对干细胞分化进行调控^{[9, 14, 15]}。然而, 以细胞外基质(extracellular matrix, ECM) 为代表的物理微环境逐渐成为干细胞研究的热点。如胶原蛋白、弹性蛋白构建的三维拓扑结构除了给干细胞提供物理支持外, 还通过整合素-细胞骨架力学信号传导直接调控干细胞分化方向^[16]; 乳腺上皮细胞在三维培养中能抵抗化疗药物(如紫杉醇) 及TNF/TRAIL等死亡信号, 而在二维培养中几乎丧失这种能力; 其在三维结构中的空间位置还决定能否响应表皮生长因子/肝细胞生长因子启动分支形态发生^{[17, 18]}。

相比生化刺激, 物理刺激具有3个显著的特点^[6]: 精准时空可控性(如光响应的水凝胶实现动态精确控制基质的刚度)、非侵入性(如电磁场可以控制干细胞的定向迁移等) 和动态操控性(如通过电磁大小精确操控细胞机械信号转导效率等)。突破传统生化因子依赖型的时空限制, 是设计构建组织工程支架、干细胞疗法的优化或再生医学新技术的研究和开发的新方向。

2　力学对干细胞及微环境的影响

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干细胞的力学微环境由剪切力、拓扑结构、ECM刚度、牵张力及微重力等物理因素共同构成^[19-22]。剪切力调控系统中剪切力大小、作用时程具有双向生物学效应。如随着层流剪切应力强度从0.1 Pa递增至2 Pa, MSCs面积增幅减小、形状排列定向度更高和细胞密度降低。机制上, 高层流剪切应力通过激活Ras同源基因家族成员A (Ras homolog family member A, RhoA)/Rho相关激酶(Rho-associated kinase, ROCK) 通路驱动肌动蛋白重组, 但密度降低的具体分子机制仍需进一步研究^{[23, 24]}。值得注意的是, 剪切力的动态特性(如振荡或间歇性) 与作用参数(强度、频率) 共同决定了细胞分化方向, 如高剪切力(0.022 5 Pa) 的振荡剪切力应力促进大鼠骨髓MSC的成骨分化, 低剪切力(10 mPa) 的间歇性剪切应力也可以有效增强大鼠骨髓MSC的成骨分化, 剪切力的速率同样也可以促进大鼠骨髓MSC向成骨或成软骨细胞分化^[23]。多壁碳纳米管涂层通过模拟ECM纳米拓扑结构, 显著提高小鼠胚胎干细胞黏附、伸展, 并促进了神经分化和神经网络的形成^[25]; 高ECM刚度通过Yes相关蛋白/PDZ结合基序转录共激活因子(Yes-associated protein/transcriptional coactivator with PDZ-binding motif, YAP/TAZ) 和扭转型转录因子1 (twist-related protein 1, TWIST1) 通路促进肿瘤侵袭, 具体机制包括YAP/TAZ的核定位、TWIST1的磷酸化和核转位激活上皮间质转化, 增强肿瘤干细胞自我更新能力, 协同推动肿瘤恶性进展^[26]。上述结果阐明力学参数通过时空特异性信号转导网络调控细胞生物学行为的分子机制。这些力学信号通过以下3类核心机械感受器传递至细胞内。

2.1　整合素介导的信号通路

整合素是细胞表面的跨膜受体, 介导细胞与ECM的相互作用, 将外界的机械刺激(如剪切力、牵张力、基质刚度) 转化为细胞内化学信号, 调控干细胞的形态调整、增殖和定向分化。机制上, 整合素通过黏着斑复合物激活下游信号通路, 传递至细胞核, 影响转录因子活性, 调控基因表达^{[23, 24]}。表面化学(如氨基、羧基、磷酸基团) 和基质刚度共同影响人MSCs的黏附、形态和分化方向。磷酸基修饰的中等刚度(41 kPa) 通过整合素-黏着斑激酶(focal adhesion kinase, FAK) 信号显著增强成骨标志物, 而羧基修饰的低刚度抑制机械张力, 诱导神经分化, 证实机械-化学信号协同决定干细胞命运^[27]。

2.2　PIEZO1离子通道

压电型机械敏感离子通道组件1 (Piezo-type mechanosensitive ion channel component 1, PIEZO1) 是机械敏感的Ca²⁺通道, 感知细胞膜张力、剪切力或基质刚度, 调控干细胞增殖、分化和组织发育。在MSCs中, PIEZO1激活导致Ca²⁺内流, 抑制Notch信号通路, 促进细胞周期蛋白磷酸化; 同时调控成骨基因表达影响骨分化; 在胚胎干细胞中, PIEZO1可能参与早期发育中的机械信号传导, 调控血管生成和心脏瓣膜形成^{[26, 28]}。

2.3　细胞骨架-YAP/TAZ通路

YAP/TAZ是机械敏感转录共激活因子, 通过感知细胞骨架张力、ECM刚度和细胞几何形状变化, 调控细胞增殖、分化和组织稳态。在MSCs中, ECM刚度通过Rho GTP酶和肌动球蛋白细胞骨架张力激活YAP/TAZ核定位, 促进成骨分化; 反之, 软基质或受限铺展面积抑制YAP/TAZ活性, 诱导脂肪生成^[15]。细胞感知和响应微环境中的力学信号, 与微环境形成生物力学相互作用, 这一机制构成了细胞-微环境互作的力学基础。在二维培养中, 干细胞具备的可塑性受限于基质平面, 而三维培养通过仿生模拟ECM拓扑构成与局部刚度梯度, 增强细胞对力学感知能力^{[8, 29]}。在三维微环境中, 通过调节核形态和染色质空间排布, 可能激活YAP/TAZ信号通路, 进而影响染色质重塑^[8]。

围绕上述机制, 再生医学提出3种抑制策略, 第一, 通过微流控建立机械刚度梯度微环境调节MSCs在高刚度区向成骨分化的迁移^[26]; 第二, 通过三维ECM拓扑结构和调节RhoA活性实现调控细胞骨架蛋白的异常重排^[29]; 第三, 直接阻断力学信号枢纽YAP/TAZ的核定位或调节RhoA-GTP酶活性, 可破坏由硬基质诱导的正反馈刺激成骨分化^[20], 为干细胞组织再生提供微环境重构、细胞命运调控的新策略。该领域的研究范式在疾病模型中同样具有重要启示。以进行性肺纤维化为例(图1), 肺泡再生障碍引发机械张力持续升高, 刺激肺泡干细胞(AT2细胞) 上的机械应力感受器(整合素α-V), 释放储存的TGFβ配体, 诱导SMAD2磷酸化并形成促纤维化。实验表明, 通过降低肺泡机械张力(如假体植入) 或靶向阻断TGFβ信号通路(如整合素α-V抑制剂GSK3008348), 可有效抑制纤维化进程。这种结合机械微环境干预与分子信号调控的双靶向治疗策略, 可能成为新型治疗方向^[30]。

3　电磁场对干细胞及微环境的影响

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电磁场(electromagnetic field, EMF) 通过多种方式调节干细胞生物学行为。一方面, 基于干细胞电生理特性跨膜电传递的跨膜信号, 在多种干细胞(如MSCs、表皮干细胞) 施加低频EMF (< 100 Hz) 后, 改变细胞膜电位激活电压门控型钙通道, 产生钙离子内流, 形成细胞内的钙振荡(0.1~1 Hz)^[31]。钙离子振荡又可激活钙调蛋白、cAMP、一氧化氮合酶等信号分子, 进而触发Wnt/β-catenin、NO/cGMP/PKG等通路, 促进正常骨髓间充质干细胞的成骨分化和血管生成, 同时抑制肿瘤干细胞增殖并诱导凋亡^[31-34]。

在参数效应关系方面, 频率、强度和时间的参数效应呈现依赖性。低频电磁场(1 mT, 30~50 Hz) 激活Wnt/β-catenin信号通路促进MSCs成骨分化。如30/45 Hz (1 mT) 的条件刺激脂肪间充质干细胞(adipose-derived stem cells, ASCs) 后, 矿化结节形成增加2.1倍, 成骨关键转录因子的mRNA水平较对照组升高3.5倍^[35-37]。而高频射频场(1.71 GHz) 则通过ERK1/2信号通路诱导胚胎干细胞来源的神经祖细胞分化, 上调βⅢ微管蛋白等神经元标志物^[38]。除了频率依赖性效应外, 还有时间依赖性效应。6 h射频场(1.71 GHz) 刺激可诱导DNA双链断裂, 并短暂激活PI3K/Akt通路, 加速细胞周期G1/S期转换^[38]; 但超过48 h未观察到显著损伤。如果时间再延长, 连续7天低频场(50 Hz, 5 mT) 刺激促进表皮干细胞增殖^[31]; 而14天脉冲场(7.5 Hz) 刺激MSCs后, Bcl-2/Bax比值上升, 钙沉积量增加^[37]。

电磁调控具有多信号联合作用的特点。在成软骨分化过程中, 50 Hz/1 mT电磁场通过激活钙振荡下游信号通路(如Wnt/β-catenin、FAK、ERK), 促进成软骨分化^{[32, 37]}。此外, 机械微环境与EMF存在协同效应, 研究表明高刚性基质联合1 mT EMF可通过增强YAP/TAZ核定位活性进一步放大成骨信号^[32]。基于上述多重调控机制, EMF在组织工程中展现明确治疗价值。低频(30~300 kHz) 和极低频(3~30 Hz) 的EMF可以刺激成骨, 增加骨密度和保护软骨, 在临床上应用于骨折愈合、骨关节炎治疗和减轻疼痛^[32], 而高频EMF通过钙超载和ROS过量, 导致肿瘤细胞DNA损伤和程序性坏死, 抑制转移和增殖^{[32, 35, 39, 40]}。

当前该领域面临三大转化挑战。首先, 定量统一性, 目前现有的研究包含了1 Hz至10 kHz频段和0.1至10 mT强度范围内的电磁能量, 但迫切需要具有更高定量化和可预测性的剂量-反应关系指导规范; 其次, 毒性相关的安全性问题, 可能随长时间使用而造成细胞遗传学不稳定, 有必要开展风险相关研究; 最后, 多模式相互作用, 特别是EMF与周围细胞环境拓扑、流动剪切应力等相关方面问题, 通过类器官芯片和多尺度模拟模型的开展而更好地阐述。

4　光照与干细胞的光生物调控

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光生物调控(photobiomodulation, PBM) 是以特定的波长、一定的光强及适当的时间为主要参数的非侵入性技术, 通过调节干细胞行为实现组织修复与再生。研究表明, 不同光谱的PBM可通过差异化的分子机制调控干细胞命运。在糖尿病创面治疗中, 单独使用脂肪间充质干细胞疗效有限, 但联合890 nm近红外光照射后, 通过协同调控炎症反应、促进血管新生及激活生长因子通路, 创面愈合率显著提升^[41]。在神经干细胞调控领域, 530 nm绿光可通过激活高表达的细菌视紫红质(highly expressible bacteriorhodopsin, HEBR) 的质子泵功能, 诱导线粒体代谢抑制、细胞周期停滞和定向分化, 该效应严格依赖于HEBR的完整活性, 而质子泵功能缺陷的突变型HEBR-D83N则完全丧失光响应能力^[42]。对于软骨修复, 660 nm红光以18 J·cm^-2的能量密度照射可显著增强半月板来源干细胞的增殖活性、软骨分化潜能及线粒体功能, 其分子机制涉及PI3K/Akt/mTOR和TGFβ3信号通路的协同激活^[43]。1 064 nm近红外光通过增强线粒体活性、增加ATP生成并降低活性氧水平, 显著抑制人MSCs的成脂分化, 这为光生物调节调控干细胞命运提供了新机制依据^[44]。这些研究充分揭示PBM技术的多重作用维度, 其效应高度依赖于光参数的精准选择和靶细胞的特异性响应机制。

光生物调节通过多维度协同机制调控干细胞命运并促进组织修复, 其作用机制主要包括4个方面: ①通过激活线粒体代谢增强细胞能量供给; ②调控关键信号通路包括PI3K/Akt/mTOR通路和Ca²⁺/ROS信号级联; ③介导表观遗传修饰如组蛋白H3K9位点乙酰化; ④协同物理微环境调控细胞力学响应。典型应用如诱导脐带间充质干细胞定向分化: 采用690 nm激光联合光敏剂的干预策略, 可通过增强线粒体活性和钙信号转导激活细胞分化程序, 同时结合胶原微岛的特定几何形貌(通过调控细胞骨架重排和细胞核形态重塑) 实现神经/脂肪谱系定向分化^{[45, 46]}。值得注意的是, 该技术通过双重调控机制加速上皮修复^[47]: 一方面通过提高H3K9乙酰化水平促进染色质解凝聚, 另一方面激活mTOR信号并上调自我更新相关蛋白BMI1表达, 同时降低ALDH阳性促分化干细胞比例, 从而维持干细胞池稳态。目前该技术已在骨骼肌、肺等多组织微环境中验证其调控效能, 并在神经精神疾病、眼科角膜修复及皮肤创面愈合等领域的临床试验中取得显著成效^[48]。

目前临床转化证据表明PBM具有双向调控作用。通过三维琼脂糖培养模型发现, 在营养缺陷(5%胎牛血清) 条件下, 光生物调节显著增强人牙髓干细胞的成骨、成脂及成软骨多向分化能力^[49]。在皮肤组织层面, UV照射的生物学效应呈现显著剂量依赖性。如图2所示, 中等强度UV (20 mJ·cm^-2) 作用于表皮最内层基底层(深蓝色区域), 通过激活该层的表皮干细胞, 经p53/p21信号通路促进再生; 而过量UV (100 mJ·cm^-2) 穿透至基底膜(浅灰色区域), 损伤其胶原Ⅳ网络, 并刺激基底层的黑素细胞(粉色区域) 异常增殖, 显著提高黑色素瘤风险^{[50, 51]}。目前的主要挑战集中在如何建立参数规范化问题(当前波长范围400~1 200 nm, 光强跨度可达10³数量级), 需构建整合PBM技术与机器学习的剂量-效应关系预测模型; 以及长期生物安全的测试, 还迫切需要完善线粒体DNA损伤的实时测量技术和多物理场耦合的机制研究^[45]。

5　多物理因素的协同作用

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物理因素(如力学信号、电磁场、光照等) 作用于干细胞的微环境中, 不仅能独立调控干细胞行为, 而且相互作用对干细胞增殖、分化和迁移等也具有更加复杂和深远的影响^{[41, 48]}。力学信号可通过整合素、细胞骨架等对干细胞进行机械感应, 电磁场通过激活电压门控钙离子通道, 进而影响细胞内钙离子水平来间接调控细胞行为, 当其与光联合作用时则可明显提高干细胞的增殖能力以及向特定方向分化的能力, 低频电磁场联合660 nm光照促进半月板源干细胞的软骨分化可通过PI3K/Akt与TGFβ信号通路的激活实现^{[43, 45]}。将两种或两种以上物理因素协同作用, 可为利用干细胞治疗提供新的思路, 光遗传学技术联合电磁场可精准调控神经干细胞迁移、分化, 为神经系统疾病的治疗提供新思路, 在软骨组织修复中, 低强度超声联合光照可明显提高软骨再生效率。除了体外研究之外, 物理因素在体内同样发挥重要作用, 血管内皮干细胞在血流剪切力作用下, 激活PI3K/Akt信号通路, 诱导分化为成熟内皮细胞; 骨骼肌干细胞在运动负荷下通过整合素-ERK通路激活增殖与肌纤维修复。表1总结了力学、电磁场、光生物调控及多因素协同作用的生物力学调节机制与治疗应用, 系统呈现了物理因素通过关键信号通路(如整合素-FAK/Rho、Wnt/β-catenin、PI3K/Akt/mTOR等) 对干细胞行为的调控模式及其在骨再生、神经修复等领域的应用潜力。总的来讲, 多物理因素协同作用发挥巨大优势的同时, 仍有一些问题需要克服, 如参数的优化、安全性等方面的不成熟, 今后的研究还应该突出组合最佳参数(如强度、频率、波长等), 以及多因素干预对组织深部的影响。

6　总结与展望

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本文综述力学刺激、电磁场、光等物理因素调控干细胞命运的最新研究进展, 物理因素通过YAP/TAZ等信号通路、Piezo通道等机械敏感分子精确调控干细胞增殖、分化和迁移等重要行为, 多物理因素协同调控凸显应用前景, 如电磁场与力学刺激联合显著提高神经干细胞分化, 光与力学信号共同刺激对骨再生修复和神经再生修复发挥更高的疗效。

尽管多物理因素在再生医学领域有着广泛的应用潜力, 但其从基础研究到临床上的转化仍有多重难关, 比如, 如何对物理参数(频率、强度、波长等) 实现精准调控使其在复杂的体内微环境中产生有效的物理刺激还是难题。生物学个体的差异对物理刺激的生物学响应不同, 制定一般适用的治疗策略非常困难, 而且物理因素治疗的长期安全、有无毒副作用尚需大规模的临床试验证明。对于上述问题, 未来可以进行可植入式微型电磁场产生器的设计, 解决体内刺激的定位问题; 同时针对脊髓损伤患者设计光遗传学联合动态支架的“光-力”协同治疗方案; 建立电磁场参数(如频率、强度) 与组织深度的剂量-效应关系数据库。对于物理因素作用的分子机制, 应该进一步了解, 并且将协同调控网络中多物理因素的动态作用研究机制进行开发, 如温敏水凝胶可以通过温度的改变动态改变力学信号, 或者光响应纳米颗粒进行局部物理刺激的靶向释放等, 为干细胞提供可实时感知并可以精确释放物理刺激的载体, 为优化治疗方案提供新的想法和途径, 通过与微流控技术结合3D打印等设备相连等, 可以构建更为精细的干细胞微环境模型, 模拟更为真实的体内生理条件, 进一步提高治疗效果。

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2025年第60卷第6期

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doi: 10.16438/j.0513-4870.2025-0060

接收时间：2025-01-17
首发时间：2026-09-20
出版时间：2025-06-12

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收稿日期：2025-01-17
修回日期：2025-03-05

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浙江大学医学院, 浙江杭州 310058

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杨隽, E-mail: yang_jun@zju.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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