Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia
Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia
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已启动的 3D 可注射微生态位可实现低剂量细胞治疗严重肢体缺血
DOI：
10.1073/pnas.1411295111
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发表时间：
2014-09-16
影响因子：
11.1
通讯作者：
Du, Yanan
中科院分区：
文献类型：
--
作者：
Li, Yaqian;Liu, Wei;Du, Yanan
意义 迫切需要最佳的细胞递送策略来增强细胞治疗的特异性、功效和可重复性，从而最大限度地减少细胞剂量和副作用。在这里，我们通过开发基于生物相容性和可生物降解的明胶微冷冻凝胶的可注射 3D 微型细胞生态位（微生态位）来解决这一未满足的需求。与基于游离细胞的疗法相比，在小鼠模型的严重肢体缺血 (CLI) 治疗中，证明了通过引发的 3D 微生态位实现的细胞保留、存活和治疗效果的显着改善。据我们所知，这是可注射和引发的细胞递送策略的首次令人信服的演示，在小鼠模型中以最低的细胞剂量治疗 CLI，实现了卓越的治疗效果。细胞疗法修复和恢复受损组织或器官的前景依赖于施用大剂量的细胞，但由于病变部位的细胞损失和死亡无法控制，其治疗效果仍然有限，有时甚至无法重现。使用大量的治疗细胞会增加细胞处理的成本和副作用的风险。因此，迫切需要最佳的细胞递送策略来增强细胞治疗的特异性、功效和可重复性，从而最大限度地减少细胞剂量和副作用。在这里，我们通过开发基于可生物降解明胶微冷冻凝胶 (GM) 的可注射 3D 微型细胞生态位 (microniche) 来解决这一未满足的需求。这些微生态位由体外引发的人类脂肪源性间充质干细胞（hMSC）组成，这些细胞接种在 GM 内，从而形成具有丰富的细胞外基质和增强的细胞间相互作用的组织样整体。与游离细胞疗法相比，在小鼠模型的严重肢体缺血（CLI）治疗中，引发的3D微生态位促进了细胞在注射过程中免受机械损伤的保护，以及体内细胞保留、存活和最终治疗功能。特别是，使用105个hMSC进行的基于3D微生态位的治疗比使用106个自由注射的hMSC进行的治疗实现了更好的缺血性肢体挽救，这是文献中治疗CLI具有治疗效果的最小剂量。据我们所知，这是可注射和引发的细胞递送策略的首次令人信服的演示，在小鼠模型中以最低的细胞剂量实现了治疗 CLI 的卓越疗效。这项研究提供了一种广泛适用的细胞输送平台技术，以提高细胞再生疗法的治愈能力。
Significance Optimal cell delivery strategies are in urgent need to enhance the specificity, efficacy, and reproducibility of cell therapy leading to minimized cell dosage and side effects. Here, we addressed this unmet need by developing injectable 3D microscale cellular niches (microniches) based on biocompatible and biodegradable gelatin microcryogels. Dramatic improvement in cell retention, survival, and therapeutic effects enabled by the primed 3D microniches was demonstrated in treatment of critical limb ischemia (CLI) in mouse models compared with the free cell-based therapy. To the best of our knowledge, this is the first convincing demonstration of injectable and primed cell delivery strategy realizing superior therapeutic efficacy with the lowest cell dosage for treating CLI in mouse model. The promise of cell therapy for repair and restoration of damaged tissues or organs relies on administration of large dose of cells whose healing benefits are still limited and sometimes irreproducible due to uncontrollable cell loss and death at lesion sites. Using a large amount of therapeutic cells increases the costs for cell processing and the risks of side effects. Optimal cell delivery strategies are therefore in urgent need to enhance the specificity, efficacy, and reproducibility of cell therapy leading to minimized cell dosage and side effects. Here, we addressed this unmet need by developing injectable 3D microscale cellular niches (microniches) based on biodegradable gelatin microcryogels (GMs). The microniches are constituted by in vitro priming human adipose-derived mesenchymal stem cells (hMSCs) seeded within GMs resulting in tissue-like ensembles with enriched extracellular matrices and enhanced cell–cell interactions. The primed 3D microniches facilitated cell protection from mechanical insults during injection and in vivo cell retention, survival, and ultimate therapeutic functions in treatment of critical limb ischemia (CLI) in mouse models compared with free cell-based therapy. In particular, 3D microniche-based therapy with 105 hMSCs realized better ischemic limb salvage than treatment with 106 free-injected hMSCs, the minimum dosage with therapeutic effects for treating CLI in literature. To the best of our knowledge, this is the first convincing demonstration of injectable and primed cell delivery strategy realizing superior therapeutic efficacy for treating CLI with the lowest cell dosage in mouse models. This study offers a widely applicable cell delivery platform technology to boost the healing power of cell regenerative therapy.