title: Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia.
abstract: 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 10(5) hMSCs realized 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.
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, People's Republic of China;
authors.forename: Yaqian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China;
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Yang
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Simin
authors.initials: S
authors.lastname: Zuo
authors.affiliation: School of Biological Science and Medical Engineering, Beihang University, Beijing 100084, People's Republic of China;
authors.forename: Siyu
authors.initials: S
authors.lastname: Feng
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Qi
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Bingjie
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Medicine, Biomaterials Innovation Research Center, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139; Harvard-Massachusetts Institute of Technology Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115; Department of Maxillofacial Biomedical Engineering and Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul 130-701, Republic of Korea; and Department of Physics, King Abdulaziz University, Jeddah 21569, Saudi Arabia.
authors.forename: Ali
authors.initials: A
authors.lastname: Khademhosseini
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China;
authors.forename: Jing
authors.initials: J
authors.lastname: Bai
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, People's Republic of China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, People's Republic of China; duyanan@tsinghua.edu.cn.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Du
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D059985:Cryogels / Q000494:pharmacology; D005355:Fibrosis; D005453:Fluorescence; D005780:Gelatin / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply* / Q000473:pathology*; D006801:Humans; D007267:Injections; D007511:Ischemia / Q000473:pathology / Q000628:therapy*; D023821:Limb Salvage; D008163:Luminescent Measurements; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009132:Muscles / Q000187:drug effects / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D055153:Stem Cell Niche
chemical_list: D043925:Angiogenesis Inducing Agents; D059985:Cryogels; D005780:Gelatin