Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia

2014 
f Harvard-Massachusetts 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 irreproduc- ible 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 strate- gies are therefore in urgent needto 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 bio- degradable gelatin microcryogels (GMs). The microniches are consti- tutedbyin vitro priminghuman adipose-derived mesenchymal stem cells (hMSCs) seeded within GMs resulting in tissue-like ensembles with enriched extracellular matrices and enhanced cell-cell interac- tions. The primed 3D microniches facilitated cell protection from mechanical insults during injection and in vivo cell retention, sur- vival, and ultimate therapeutic functions in treatment of critical limb ischemia (CLI) in mouse models compared with free cell-based ther- apy. In particular, 3D microniche-based therapy with 10 5 hMSCs re- alized better ischemic limb salvage than treatment with 10 6 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.
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