肝脏脱细胞生物支架的制备及诱导骨髓间充质干细胞肝向分化的研究
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摘要
肝移植是目前针对终末期肝病的有效治疗方式。然而，供肝短缺、手术并发症、慢性排斥反应和医疗成本高等限制因素迫使研究者开始寻求新的替代治疗，并诞生了肝脏组织工程和再生医学这一新兴研究领域。在过去的数十年中，尽管研究人员在仿生三维动态培养方面取得了较大进展，但仍难于完全模仿肝脏细胞外基质（ECM）的复杂微环境。目前，全器官脱细胞支架正逐渐受到研究者的关注。脱细胞是指去除脏器中细胞成分，并且最大程度地保留脏器的大体形态、ECM成分和超微结构。一些研究成功地将功能性实质细胞或特定干/祖细胞种植于脱细胞ECM，为组织工程和再生医学研究提供新的研究平台。
脱细胞支架研究的一个难题是脱细胞方案的选择和优化。近年来，研究人员已通过比较研究对心脏、肾脏、肺和膀胱等器官的脱细胞方案进行了改进。目前，文献中已报道了多种方案制备脱细胞肝支架（DLB），但尚无研究对上述方案制备DLB的理化性质、细胞相容性和免疫原性进行比较。该研究领域的另一难题是如何获取足够数量且功能完备的肝细胞。由于自体肝组织获取和体外维持肝细胞特性等方面存在困难，从干/祖细胞获取肝细胞成为目前该领域关注的研究热点。其中，间充质干细胞（MSCs）被认为是最具治疗潜力的细胞类型之一。目前已有多项研究证实了MSCs在特定培养条件下可诱导分化为类肝细胞。但诱导成功率较低，并且诱导的类肝细胞只具有成熟肝细胞的部分标志物和功能。因此，对MSCs肝向分化诱导方案和培养条件还需要进一步研究。近期一些研究证实组织特异性ECM可促进干/祖细胞定向分化。本研究将探讨DLB是否能够体外诱导MSCs向肝系细胞分化。
本研究利用三种文献报道的洗脱方案（CHAPS、SDS和Triton X-100方案）和一种新建立的方案（NP-40方案）制备大鼠DLB，全面评估DLB的结构特点和生化特性及其细胞相容性和免疫原性，为DLB制备方案的改进提供依据；本课题还利用大鼠DLB制成的三维支架，为小鼠MSCs提供体外培养和诱导分化微环境，为体外高效诱导MSCs向肝系细胞分化寻找新的方法；最后，将体外预分化的MSCs移植给CCl4致肝纤维化小鼠，进一步观察DLB体外诱导分化MSCs的在体功能，并对其治疗作用机制进行探讨。
主要研究成果如下：
1.除CHAPS方案外，SDS、Triton X-100和NP-40方案均成功制备出符合脱细胞标准的大鼠DLB，但不同方案制备的DLB在超微结构、ECM成分、细胞相容性和免疫原性存在明显差异；与SDS和Triton X-100方案相比，NP-40方案制备的DLB具有更好的细胞支持作用和体内重塑结局；另外，统计学分析发现DLB体内重塑结局与DNA残留量、M2巨噬细胞数量和M2:M1细胞比值具有显著相关性。
2.从GFP基因敲入C57BL/6小鼠体内成功分离和培养出骨髓干细胞，表达MSCs的细胞形态和表面标志物；NP-40制备的DLB为种植的MSCs提供了三维生长微环境；与DLB和培养瓶（TCF）静止培养相比，动态培养的DLB显著提高MSCs的细胞存活率和增殖速度。
3.动态培养肝支架（DCS）本身或联合肝细胞诱导生长因子（GF），均能体外诱导MSCs向肝系细胞分化；与TCF培养相比，DCS培养的细胞表达更高水平的肝细胞标志物（AFP、ALB、CK7、CK8、CK9、CK19、肝细胞转录因子和肝细胞代谢酶等），并具有更强的肝细胞相关合成和代谢功能（分泌AFP和ALB、代谢尿素、合成糖原、摄取吲哚氰绿和低密度脂蛋白），以及具有成熟肝细胞超微结构特点。
4.与未分化MSCs相比，体外利用GF预处理或DCS联合GF预处理的MSCs在移植给CCl4致肝纤维化小鼠后显著改善小鼠生存率、肝脏功能和纤维化程度；其中DCS联合GF预处理MSCs的归巢效率最高。定植到肝脏的预分化MSCs主要通过旁分泌作用抑制肝星状细胞活化、刺激内源性肝细胞增殖，达到修复肝损伤的目的。
上述结果表明，本研究建立了一种新的肝脏脱细胞方案，制备的DLB具有良好的细胞相容性和较低的免疫原性；这种DLB在动态培养条件下可以高效地诱导MSCs向类肝细胞分化、表达更加稳定和丰富的肝细胞功能，并在移植体内后对慢性肝损伤具有较好的治疗作用。总之，这种肝脏脱细胞支架为肝脏组织工程和再生医学提供了一个全新的研究平台，有望为临床治疗终末期肝病提供新的治疗手段。
Liver transplantation remains the definitive treatment option for end-stage liver dis-eases. However, the surgical complications, chronic rejections, critical shortage of donororgans and high cost of this procedure have sparked tremendous interest in finding newtreatments. Liver tissue engineering and regenative medicine have emerged as alternativetherapies. Within the past decade, most of the major achievements in these fields have in-volved the production of mimic biological microenvironment that provides appropriatesignals for regulating cellular behavior, which however remains exceedingly difficult toachieve using currently available synthetic or natural materials. There has been an in-creasing emphasis on the use of acellular whole-organ matrices, which can be prepared byremoving the cellular components from donor organs in a process referred to as decellula-rization. Decellularization largely preserves the native composition, ultrastructure and macroscopic three-dimensional architecture of the native extracellular matrix (ECM).Numerous studies have shown that an acellular ECM can be seeded with either functionalparenchymal cells or a specific stem/progenitor cell population, providing initial steps inthe development of new approaches.
One of the many challenges in this strategy is the optimization of donor organ decel-lularization. Recently, improved decellularization protocols have been established for exvivo organs, such as the heart, kidney, lung and bladder. A comparison of both the struc-tural and biochemical properties of the ECM scaffold as well as the cell-supporting poten-tial provides relatively ideal scaffolds for further investigation. Currently, decellularizedliver bioscaffold (DLB) is obtained using several different strategies. However, the optim-al technique for liver decellularization has not yet been determined.
Another challenge is the supply of functional hepatocytes due to the difficulties asso-ciated with obtaining autologous hepatic tissue and maintaining the phenotype of the pri-mary hepatocytes in culture. Increasing evidence suggests that the differentiation of me-senchymal stem cells (MSCs) into hepatocytes is achieved in the appropriate microenvi-ronment. However, the several traditional protocols used to date have had limited success,and these hepatocyte-like cells exhibit only a portion of the markers and functions of pri-mary hepatocytes. Therefore, further investigations are needed to optimize the direct dif-ferentiation protocol and the culture conditions for MSCs to yield mature hepatocyte-likecells that are fully functional. Recently, studies have emphasized that the differentiation ofstem/progenitor cells is lineage restricted by the tissue-specific biomatrix scaffold. Thisstudy investigates whether DLB promotes the hepatic differentiation of MSCs.
In the present study, we comprehensively assessed the structural and biochemicalproperties of rat DLB resulting from four different protocols, with the aim to determine arelatively optimized method for the derivation of DLB with the most positive host re-modeling response and cytocompatibility. We hypothesized that the optimized DLB pro-motes the hepatic differentiation of murine MSCs into high yields of mature hepatocytesin vitro. Furthermore, the therapeutic potential and cell derivation of the pre-differentiatedcells in vitro was investigated in vivo following the intravenous administration of the cellsin a model of chronic liver injury.
The main finds are as follows:
1. We characterized DLBs treated using four different decellularization methods todetermine the most effective strategy for the derivation of rat DLB. Althought3-[(3-Cholamidopropyl) dimethylammonio] propanesulfonate (CHAPS) proved inefficientfor the decellularization of rat livers, the other three methods, which are primarily basedon sodium dodecyl sulfate, Triton X-100and nonyl phenoxylpolyethoxylethanol (NP-40)combined with enzymes, successfully yielded DLBs with distinct ultrastructure, ECMcomposition, cell-supporting potential in vitro, and remodeling results as well as patternsof macrophage polarization in vivo. The NP-40-based strategy resulted in a relatively op-timized DLB with enhanced cytotoxicity and host remodeling results. Furthermore, thehost remodeling results statistically correlated with the residual DNA, the number of M2macrophages and the M2:M1cell ratio
2. For hepatocyte differentiation, bone marrow derived MSCs isolated fromGFP-transgenic C57BL/6mice possessed the basic features of MSCs as demonstrated bycell morphology and flow cytometry. Results of biocompatibility indicated that DLBtreated with NP-40-based protocol promoted significantly better MSCs cell viability andproliferation in dynamic culture with optimal flow rate during a3-week differentiation pe-riod, when compared to the biomatrix scaffold cultured in static or the monolayer staticculture system.
3. The dynamic cultured bioscaffold (DCS), either on its own or in combination withhepatic growth factors (GF), induced the lineage-specific differentiation of MSCs into he-patocyte-like cells expressed hepatocyte-specific markers [eg, α-fetoprotein (AFP), albu-min (ALB), cytoketatins (CK7, CK8, CK18, CK19), hepatic-enriched transcription factors,hepatic functional marker genes and metabolic enzymes] at mRNA and protein levels.Most markers were expressed in DCS group earlier than in the control group. The signifi-cantly higher synthetic and metabolic functions [AFP and ALB secretion, Urea production,glycogen storage, the uptake of indocyaine green and low-density lipoprotein] and the ul-trastructural characteristics of the hepatocyte-like cells in the DCS group further demon-strated the important role of the bioscaffold.
4. After the systemic transplantation into a mouse model of CCl4-induced liver fibro-sis, when compared with undifferentiated MSCs or MSCs differentiated using GF alone,the pre-differentiated MSCs produced using the bioscaffold method combined with GF in vitro facilitated the survival of the mice, liver restoration and the long-term functional he-patic integration in vivo. Cell engraftment was significantly improved using thepre-differentiated MSCs by the DCS compared to cells induced in the TCF and the undif-ferentiated MSCs. The inactivation of hepatic stellate cells and the repopulation the resi-dential hepatocytes were promoted by the transplantation of MSCs that were wellpre-differentiated in vitro.
In summary, we developed a novel NP-40-based decellularization strategy for thesuccessful derivation of rat DLB, which resulted in the improved cytotoxicity in vitro andhost remodeling results in vivo. In addition, we demonstrated that MSCs could be con-verted into functional hepatocyte-like cells through induction using DLB. As comparedwith the2D conventional induction, these hepatocyte-like cells exhibited higher level andmore stable functions that are potentially useful for the treatment of chronic liver damage.The present study indicates that the3D liver biomatrix might have considerable potentialfor cell-based therapy and tissue engineering.
脱细胞支架研究的一个难题是脱细胞方案的选择和优化。近年来，研究人员已通过比较研究对心脏、肾脏、肺和膀胱等器官的脱细胞方案进行了改进。目前，文献中已报道了多种方案制备脱细胞肝支架（DLB），但尚无研究对上述方案制备DLB的理化性质、细胞相容性和免疫原性进行比较。该研究领域的另一难题是如何获取足够数量且功能完备的肝细胞。由于自体肝组织获取和体外维持肝细胞特性等方面存在困难，从干/祖细胞获取肝细胞成为目前该领域关注的研究热点。其中，间充质干细胞（MSCs）被认为是最具治疗潜力的细胞类型之一。目前已有多项研究证实了MSCs在特定培养条件下可诱导分化为类肝细胞。但诱导成功率较低，并且诱导的类肝细胞只具有成熟肝细胞的部分标志物和功能。因此，对MSCs肝向分化诱导方案和培养条件还需要进一步研究。近期一些研究证实组织特异性ECM可促进干/祖细胞定向分化。本研究将探讨DLB是否能够体外诱导MSCs向肝系细胞分化。
本研究利用三种文献报道的洗脱方案（CHAPS、SDS和Triton X-100方案）和一种新建立的方案（NP-40方案）制备大鼠DLB，全面评估DLB的结构特点和生化特性及其细胞相容性和免疫原性，为DLB制备方案的改进提供依据；本课题还利用大鼠DLB制成的三维支架，为小鼠MSCs提供体外培养和诱导分化微环境，为体外高效诱导MSCs向肝系细胞分化寻找新的方法；最后，将体外预分化的MSCs移植给CCl4致肝纤维化小鼠，进一步观察DLB体外诱导分化MSCs的在体功能，并对其治疗作用机制进行探讨。
主要研究成果如下：
1.除CHAPS方案外，SDS、Triton X-100和NP-40方案均成功制备出符合脱细胞标准的大鼠DLB，但不同方案制备的DLB在超微结构、ECM成分、细胞相容性和免疫原性存在明显差异；与SDS和Triton X-100方案相比，NP-40方案制备的DLB具有更好的细胞支持作用和体内重塑结局；另外，统计学分析发现DLB体内重塑结局与DNA残留量、M2巨噬细胞数量和M2:M1细胞比值具有显著相关性。
2.从GFP基因敲入C57BL/6小鼠体内成功分离和培养出骨髓干细胞，表达MSCs的细胞形态和表面标志物；NP-40制备的DLB为种植的MSCs提供了三维生长微环境；与DLB和培养瓶（TCF）静止培养相比，动态培养的DLB显著提高MSCs的细胞存活率和增殖速度。
3.动态培养肝支架（DCS）本身或联合肝细胞诱导生长因子（GF），均能体外诱导MSCs向肝系细胞分化；与TCF培养相比，DCS培养的细胞表达更高水平的肝细胞标志物（AFP、ALB、CK7、CK8、CK9、CK19、肝细胞转录因子和肝细胞代谢酶等），并具有更强的肝细胞相关合成和代谢功能（分泌AFP和ALB、代谢尿素、合成糖原、摄取吲哚氰绿和低密度脂蛋白），以及具有成熟肝细胞超微结构特点。
4.与未分化MSCs相比，体外利用GF预处理或DCS联合GF预处理的MSCs在移植给CCl4致肝纤维化小鼠后显著改善小鼠生存率、肝脏功能和纤维化程度；其中DCS联合GF预处理MSCs的归巢效率最高。定植到肝脏的预分化MSCs主要通过旁分泌作用抑制肝星状细胞活化、刺激内源性肝细胞增殖，达到修复肝损伤的目的。
上述结果表明，本研究建立了一种新的肝脏脱细胞方案，制备的DLB具有良好的细胞相容性和较低的免疫原性；这种DLB在动态培养条件下可以高效地诱导MSCs向类肝细胞分化、表达更加稳定和丰富的肝细胞功能，并在移植体内后对慢性肝损伤具有较好的治疗作用。总之，这种肝脏脱细胞支架为肝脏组织工程和再生医学提供了一个全新的研究平台，有望为临床治疗终末期肝病提供新的治疗手段。
Liver transplantation remains the definitive treatment option for end-stage liver dis-eases. However, the surgical complications, chronic rejections, critical shortage of donororgans and high cost of this procedure have sparked tremendous interest in finding newtreatments. Liver tissue engineering and regenative medicine have emerged as alternativetherapies. Within the past decade, most of the major achievements in these fields have in-volved the production of mimic biological microenvironment that provides appropriatesignals for regulating cellular behavior, which however remains exceedingly difficult toachieve using currently available synthetic or natural materials. There has been an in-creasing emphasis on the use of acellular whole-organ matrices, which can be prepared byremoving the cellular components from donor organs in a process referred to as decellula-rization. Decellularization largely preserves the native composition, ultrastructure and macroscopic three-dimensional architecture of the native extracellular matrix (ECM).Numerous studies have shown that an acellular ECM can be seeded with either functionalparenchymal cells or a specific stem/progenitor cell population, providing initial steps inthe development of new approaches.
One of the many challenges in this strategy is the optimization of donor organ decel-lularization. Recently, improved decellularization protocols have been established for exvivo organs, such as the heart, kidney, lung and bladder. A comparison of both the struc-tural and biochemical properties of the ECM scaffold as well as the cell-supporting poten-tial provides relatively ideal scaffolds for further investigation. Currently, decellularizedliver bioscaffold (DLB) is obtained using several different strategies. However, the optim-al technique for liver decellularization has not yet been determined.
Another challenge is the supply of functional hepatocytes due to the difficulties asso-ciated with obtaining autologous hepatic tissue and maintaining the phenotype of the pri-mary hepatocytes in culture. Increasing evidence suggests that the differentiation of me-senchymal stem cells (MSCs) into hepatocytes is achieved in the appropriate microenvi-ronment. However, the several traditional protocols used to date have had limited success,and these hepatocyte-like cells exhibit only a portion of the markers and functions of pri-mary hepatocytes. Therefore, further investigations are needed to optimize the direct dif-ferentiation protocol and the culture conditions for MSCs to yield mature hepatocyte-likecells that are fully functional. Recently, studies have emphasized that the differentiation ofstem/progenitor cells is lineage restricted by the tissue-specific biomatrix scaffold. Thisstudy investigates whether DLB promotes the hepatic differentiation of MSCs.
In the present study, we comprehensively assessed the structural and biochemicalproperties of rat DLB resulting from four different protocols, with the aim to determine arelatively optimized method for the derivation of DLB with the most positive host re-modeling response and cytocompatibility. We hypothesized that the optimized DLB pro-motes the hepatic differentiation of murine MSCs into high yields of mature hepatocytesin vitro. Furthermore, the therapeutic potential and cell derivation of the pre-differentiatedcells in vitro was investigated in vivo following the intravenous administration of the cellsin a model of chronic liver injury.
The main finds are as follows:
1. We characterized DLBs treated using four different decellularization methods todetermine the most effective strategy for the derivation of rat DLB. Althought3-[(3-Cholamidopropyl) dimethylammonio] propanesulfonate (CHAPS) proved inefficientfor the decellularization of rat livers, the other three methods, which are primarily basedon sodium dodecyl sulfate, Triton X-100and nonyl phenoxylpolyethoxylethanol (NP-40)combined with enzymes, successfully yielded DLBs with distinct ultrastructure, ECMcomposition, cell-supporting potential in vitro, and remodeling results as well as patternsof macrophage polarization in vivo. The NP-40-based strategy resulted in a relatively op-timized DLB with enhanced cytotoxicity and host remodeling results. Furthermore, thehost remodeling results statistically correlated with the residual DNA, the number of M2macrophages and the M2:M1cell ratio
2. For hepatocyte differentiation, bone marrow derived MSCs isolated fromGFP-transgenic C57BL/6mice possessed the basic features of MSCs as demonstrated bycell morphology and flow cytometry. Results of biocompatibility indicated that DLBtreated with NP-40-based protocol promoted significantly better MSCs cell viability andproliferation in dynamic culture with optimal flow rate during a3-week differentiation pe-riod, when compared to the biomatrix scaffold cultured in static or the monolayer staticculture system.
3. The dynamic cultured bioscaffold (DCS), either on its own or in combination withhepatic growth factors (GF), induced the lineage-specific differentiation of MSCs into he-patocyte-like cells expressed hepatocyte-specific markers [eg, α-fetoprotein (AFP), albu-min (ALB), cytoketatins (CK7, CK8, CK18, CK19), hepatic-enriched transcription factors,hepatic functional marker genes and metabolic enzymes] at mRNA and protein levels.Most markers were expressed in DCS group earlier than in the control group. The signifi-cantly higher synthetic and metabolic functions [AFP and ALB secretion, Urea production,glycogen storage, the uptake of indocyaine green and low-density lipoprotein] and the ul-trastructural characteristics of the hepatocyte-like cells in the DCS group further demon-strated the important role of the bioscaffold.
4. After the systemic transplantation into a mouse model of CCl4-induced liver fibro-sis, when compared with undifferentiated MSCs or MSCs differentiated using GF alone,the pre-differentiated MSCs produced using the bioscaffold method combined with GF in vitro facilitated the survival of the mice, liver restoration and the long-term functional he-patic integration in vivo. Cell engraftment was significantly improved using thepre-differentiated MSCs by the DCS compared to cells induced in the TCF and the undif-ferentiated MSCs. The inactivation of hepatic stellate cells and the repopulation the resi-dential hepatocytes were promoted by the transplantation of MSCs that were wellpre-differentiated in vitro.
In summary, we developed a novel NP-40-based decellularization strategy for thesuccessful derivation of rat DLB, which resulted in the improved cytotoxicity in vitro andhost remodeling results in vivo. In addition, we demonstrated that MSCs could be con-verted into functional hepatocyte-like cells through induction using DLB. As comparedwith the2D conventional induction, these hepatocyte-like cells exhibited higher level andmore stable functions that are potentially useful for the treatment of chronic liver damage.The present study indicates that the3D liver biomatrix might have considerable potentialfor cell-based therapy and tissue engineering.
引文
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