Pharmacologically active microcarriers delivering BDNF within a hydrogel: Novel strategy for human bone marrow-derived stem cells neural/neuronal differentiation guidance and therapeutic secretome enhancement

• Published in: Acta biomaterialia Vol. 49; pp. 167 - 180
• Main Authors: Kandalam, Saikrishna, Sindji, Laurence, Delcroix, Gaëtan J.-R., Violet, Fabien, Garric, Xavier, André, Emilie M., Schiller, Paul C., Venier-Julienne, Marie-Claire, des Rieux, Anne, Guicheux, Jérôme, Montero-Menei, Claudia N.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2017; Elsevier BV; Elsevier
• Subjects: Aged; Angiogenesis; BDNF drug delivery; Biocompatibility; Biocompatible Materials - pharmacology; Biodegradability; Biodegradation; Bone marrow; Brain; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - pharmacology; Cell Differentiation - drug effects; Cell Shape - drug effects; Central nervous system; Chemical Precipitation; Chemokines; Differentiation; Disorders; Drug Liberation; Fibronectin; Gene Expression Regulation - drug effects; Geriatry and gerontology; Growth factors; Human health and pathology; Humans; Hydrogel, Polyethylene Glycol Dimethacrylate - chemistry; Hydrogels; Hypromellose Derivatives - chemistry; Interleukin 8; Life Sciences; Male; Mesenchymal stem cells; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal Cells - metabolism; Mesenchymal Stromal Cells - ultrastructure; Methylcellulose; Microspheres; Nanoparticles - chemistry; Nerve growth factor; Neural repair; Neurological diseases; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Pharmacology; Proteome - secretion; RANTES; Regenerative medicine; Rheology; Rhumatology and musculoskeletal system; RNA, Messenger - genetics; RNA, Messenger - metabolism; Scaffolds; Secretome; Si-HPMC hydrogel; Silanes - chemistry; Spheres; Stem cells; Studies; Tissue engineering; Vascular endothelial growth factor; Microspheres; Neural repair; BDNF drug delivery; Si-HPMC hydrogel; Mesenchymal stem cells
• ISSN: 1742-7061; 1878-7568
• DOI: 10.1016/j.actbio.2016.11.030

[Display omitted] Stem cells combined with biodegradable injectable scaffolds releasing growth factors hold great promises in regenerative medicine, particularly in the treatment of neurological disorders. We here integrated human marrow-isolated adult multilineage-inducible (MIAMI) stem cells and pharmacologically active microcarriers (PAMs) into an injectable non-toxic silanized-hydroxypropyl methylcellulose (Si-HPMC) hydrogel. The goal is to obtain an injectable non-toxic cell and growth factor delivery device. It should direct the survival and/or neuronal differentiation of the grafted cells, to safely transplant them in the central nervous system, and enhance their tissue repair properties. A model protein was used to optimize the nanoprecipitation conditions of the neuroprotective brain-derived neurotrophic factor (BDNF). BDNF nanoprecipitate was encapsulated in fibronectin-coated (FN) PAMs and the in vitro release profile evaluated. It showed a prolonged, bi-phasic, release of bioactive BDNF, without burst effect. We demonstrated that PAMs and the Si-HPMC hydrogel increased the expression of neural/neuronal differentiation markers of MIAMI cells after 1week. Moreover, the 3D environment (PAMs or hydrogel) increased MIAMI cells secretion of growth factors (b-NGF, SCF, HGF, LIF, PlGF-1, SDF-1α, VEGF-A & D) and chemokines (MIP-1α & β, RANTES, IL-8). These results show that PAMs delivering BDNF combined with Si-HPMC hydrogel represent a useful novel local delivery tool in the context of neurological disorders. It not only provides neuroprotective BDNF but also bone marrow-derived stem cells that benefit from that environment by displaying neural commitment and an improved neuroprotective/reparative secretome. It provides preliminary evidence of a promising pro-angiogenic, neuroprotective and axonal growth-promoting device for the nervous system. Combinatorial tissue engineering strategies for the central nervous system are scarce. We developed and characterized a novel injectable non-toxic stem cell and protein delivery system providing regenerative cues for central nervous system disorders. BDNF, a neurotrophic factor with a wide-range effect, was nanoprecipitated to maintain its structure and released in a sustained manner from novel polymeric microcarriers. The combinatorial 3D support, provided by fibronectin-microcarriers and the hydrogel, to the mesenchymal stem cells guided the cells towards a neuronal differentiation and enhanced their tissue repair properties by promoting growth factors and cytokine secretion. The long-term release of physiological doses of bioactive BDNF, combined to the enhanced secretion of tissue repair factors from the stem cells, constitute a promising therapeutic approach.