Considering the intrinsically limited regenerative capability of the central nervous system (CNS) and the complex inhibitory microenvironment of injured spinal cord, developing effective therapeutics for CNS diseases and injuries [e.g., Parkinson disease and spinal cord injury (SCI)] has been challenging. To this end, stem cell therapy can provide a promising solution. Neural stem cells can differentiate into neurons and restore the damaged neuronal circuits. Additionally, stem cells modulate the inhibitory microenvironment at the site of CNS disease and injury through the secretion of trophic factors. Nevertheless, the low survival rate and incomplete differentiation control of stem cells in vivo are critical barriers for the full realization of stem cell therapy potential. As such, there is an urgent need to develop an innovative approach to enhance stem cell transplantation and to control stem cell fate precisely.

Addressing these challenges, scientists from Prof. KiBum Lee’s Lab (Letao Yang, Dean Chueng, and Christopher Rathnam) have recently designed and synthesized a biodegradable hybrid inorganic (BHI) nanoscaffold assembled from MnO 2 2D nanomaterial and extracellular matrix (ECM) protein for enhanced stem cell survival and neuronal differentiation (Fig. 1, Nature Communications, 2018, DOI: 10.1038/s41467-018- 05599-2). Our hybrid nanoscaffold provides a favorable microenvironment for the transplanted stem cells, thereby enhancing stem cell transplantation. Compared to conventional 2D carbon-based nanoscaffolds, our 3D BHInanoscaffold is readily biodegraded through a bioreductant-based redox mice d9d52Fig. 1 A biodegradable hybrid inorganic (BHI) nanoscaffold for advanced stem cell therapy. This image illustrates the MnO 2 2D nanomaterial-assembled nanoscaffold for enhanced stem cell transplantation and improved treatment of murine hemisection SCI in vivo.degradation mechanism (Fig. 2). Using density functional theory (DFT) simulations, we illustrated the molecular mechanisms and provided design principles for the assembly of MnO 2 2D nanomaterials and biomolecules. Based on in vitro stem cell assays, stem cells cultured on the 3D BHI nanoscaffold demonstrated significant neuronal differentiation and axonal
elongation enhancement compared to conventional scaffolds. These results directly supported the positive role of 3D BHI nanoscaffold for stem cell fate control. By further incorporating fluorescent molecules and neurogenic drugs, we showed monitorable drug delivery and further improved neuronal differentiation of stem cells. Most importantly, the therapeutic potential of drug loaded 3D BHI nanoscaffold for enhanced stem cell transplantation and promoting functional recovery was successfully evaluated in vivo using a hemisection spinal cord injury model (Fig. 3). Collectively, our results identified a new composition for 2D and 3D tissue engineering scaffolds and showcased their unique advantages in drug delivery, stem cell therapy, and regenerative medicine. We thank our collaborators Prof. Lu Wang’s group (DFT simulations) at Rutgers CCB department and Prof. Li Cai’s group (SCI studies) at Rutgers Biomedical Engineering department for their contributions to the project. We also acknowledge financial support from NIH (1R21NS085569-01), NSF (CHE-1429062), and the New Jersey Commission on Spinal Cord (CSCR17IRG010).

kibum article bigFig. 2 Previous work on Graphene-based hybrid nanoscaffolds for neural differentiation of stem cells. a, Scheme (image on the top), scanning electron microscope (SEM, image on the middle) and immunostaining image (image on the bottom) on a mature neuronal marker (MAP2) showing the enhanced axonal alignment of neurons differentiated from human NSCs on a silica nanoparticle-graphene oxide hybrid nanoscaffold. Scale bars: 10 μm and 50 μm for the middle and bottom images, respectively. b, Scheme (image on the top), SEM (image on the middle) and fluorescent images (image on the bottom) showing the enhanced adhesion and oligodendrocytic differentiation of GFP-labelled rat neural stem cells on a nanofiber-graphene oxide hybrid nanoscaffold. Scale bars: 10 μm and 20 μm for the middle and bottom images, respectively. c, Graphene-based hybrid nanoscaffolds for enhanced neuronal differentiation. The top image is a scheme illustrating the interactions between NSCs and nanoscaffolds. The middle optical microscope image characterizes a grid-shaped graphene oxide micropattern. The bottom immunostaining image on neuronal marker (TuJ1) indicates the neuronal differentiation from mesenchymal stem cells on the graphene oxide grid-shaped micropattern. Scale bars: 50 μm.


kibum article 2Fig.3 BHI nanoscaffolds for advanced stem cell therapy. a, To develop an effective method for stem cell transplantation, we synthesized a BHI nanoscaffolds that simultaneously integrate advancements in 3D-hybrid nanomaterials and DFT simulation-based precision drug screening. Cells are labelled with green due to their green fluorescence protein labelling. Laminin proteins are colored in blue. Drugs are represented by red- colored dots. In the simulation scheme, blue colored atoms represent manganese and red colored atoms represent oxygen. b, By transplanting NSCs using 3D-BHI nanoscaffold, cell survival and neuronal differentiation were improved, which leads to a reduction of glialscar and enhanced functional recovery. c, Immunostaining images showing the survival and guided neuronal differentiation of NSCs in the SCI sites. Scale bar in the image on the left: 250 μm; Scale bar in images on the middle and right: 100 μm.


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Prof. Lee 98389Prof. Ki-Bum Lee

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