The effect of multivalent Sonic hedgehog on differentiation of human embryonic stem cells into dopaminergic and GABAergic neurons

Vazin, Tandis; Ashton, Randolph S.; Conway, Anthony; Rode, Nikhil A.; Lee, Susan M.; Bravo, Verenice; Healy, Kevin E.; Kane, Ravi S.; Schaffer, David V.

doi:10.1016/j.biomaterials.2013.10.025

Cited by 45 publications

(44 citation statements)

References 40 publications

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“…28 We have previously validated methods to effectively measure the valency of these nanoscale protein conjugates, 29 and we have demonstrated that multivalent conjugation of the growth factor Sonic hedgehog (Shh) to linear polymer chains of hyaluronic acid (HyA) yields increasing Shh-pathway activation with higher Shh valencies. 30,31 Furthermore, multivalent Shh conjugates (mvShh) induced enhanced angiogenic function relative to an equivalent dose of unconjugated Shh. 30 Taken together, mvShh conjugates are capable of increasing the per-molecule bioactivity of Shh to elicit therapeutic cellular responses of Shh at lower tissue-level concentrations.…”

Section: Introductionmentioning

confidence: 99%

Multivalent Conjugates of Sonic Hedgehog Accelerate Diabetic Wound Healing

Han

Layman

Rode

et al. 2015

Tissue Engineering Part A

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Despite their preclinical promise, few recombinant growth factors have been fully developed into effective therapies, in part, due to the short interval of therapeutic activity after administration. To address this problem, we developed nanoscale polymer conjugates for multivalent presentation of therapeutic proteins that enhance the activation of targeted cellular responses. As an example of this technology, we conjugated multiple Sonic hedgehog (Shh) proteins onto individual hyaluronic acid biopolymers to generate multivalent protein clusters at defined ratios (i.e., valencies) that yield enhanced Shh pathway activation at equivalent concentrations relative to unconjugated Shh. In this study, we investigated whether these multivalent conjugates (mvShh) could be used to improve the therapeutic function of Shh. We found that a single treatment with mvShh significantly accelerated the closure of full-thickness wounds in diabetic (db/db) mice compared to either an equivalent dose of unconjugated Shh or the vehicle control. Furthermore, we identified specific indicators of wound healing in fibroblasts and endothelial cells (i.e., transcriptional activation and cell migration) that were activated by mvShh in vitro and at concentrations approximately an order of magnitude lower than the unconjugated Shh. Taken together, our findings suggest that mvShh conjugates exhibit greater potency to activate the Shh pathway, and this multivalency advantage improves its therapeutic effect to accelerate wound closure in a diabetic animal model. Our strategy of multivalent protein presentation using nanoscale polymer conjugates has the potential to make a significant impact on the development of protein-based therapies by improving their in vivo performance.

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Section: Introductionmentioning

confidence: 99%

Multivalent Conjugates of Sonic Hedgehog Accelerate Diabetic Wound Healing

Han

Layman

Rode

et al. 2015

Tissue Engineering Part A

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“…In biomaterials research, one attractive approach is to modulate hPSC fate decisions and differentiations using small molecules that regulate signaling pathways through defined mechanisms [26][27][28][29]. Specifically, small molecules in SHH signaling [25,30] have been demonstrated previously to facilitate the generation of some specific neural types from hPSCs [31]. However, the capability of SHH-related small molecules to tune different neuronal subtypes in 3-D differentiation from hiPSCs has not been fully investigated.…”

Section: Introductionmentioning

confidence: 98%

“…In neural patterning of brain tissues, i.e., the process through which neural progenitors acquire brain regional identity, activation of sonic hedgehog (SHH) signaling induces ventral (V) identity of the developing neural ectoderm while SHH inhibition generates dorsal (D) telencephalic progenitors (i.e., affects D-V patterning) [24,25]. Thus, differential levels of SHH signaling, in combination with other signaling such as Wnt and retinoic acid, influence neural regional specification of hPSCs into forebrain cortical tissues, midbrain tissues, and hindbrain/spinal cord tissues [6].…”

Section: Introductionmentioning

confidence: 99%

Neural patterning of human induced pluripotent stem cells in 3-D cultures for studying biomolecule-directed differential cellular responses

et al. 2016

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“…The finite half-life of wild-type proteins may limit the efficacy of protein delivery for stimulating the generation and maturation of new neurons. However, we have recently engineered multivalent ligands, composed of proteins conjugated to a linear biopolymer, which cluster their cognate receptors and thereby substantially elevate signaling relative to corresponding monovalent ligands [27][28][29][30][31]. This raises the possibility that the ligands found within the stem cell niche could be integrated into highly bioactive materials and thereby begin to create a synthetic stem cell microenvironment for controlling cell fate decisions.…”

Section: Introductionmentioning

confidence: 99%

“…However, these two studies utilized single factors, and no studies have explored the potential for bioactive microenvironments to present combinations of signals to stimulate endogenous stem or progenitor cells and induce their ectopic differentiation, particularly in delicate tissues such as the CNS. Accordingly, we have engineered soluble, multivalent biomaterial conjugates harboring factors present within the naturally neurogenic hippocampus, specifically ephrin-B2 [10] and Shh [6,29], and these materials were injected into the interstitial space of both the striatum and cortex of the adult brain to create a synthetic, engineered stem cell microenvironment that stimulates the proliferation and neuronal differentiation of normally quiescent progenitor cells. Additionally, by including the chemokine stromal cell-derived factor-1a (SDF-1a), a more than fourfold increase in the basal level of neurogenesis compared with controls was observed, suggesting potential recruitment of endogenous NSCs from the neurogenic SGZ and SVZ to the normally non-neurogenic regions.…”

Section: Introductionmentioning

confidence: 99%

Biomaterial Microenvironments to Support the Generation of New Neurons in the Adult Brain

Conway

Schaffer

2014

Stem Cells

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Neural stem cells (NSC) in two regions of the adult mammalian brain-the subventricular zone (SVZ) and hippocampus-continuously generate new neurons, enabled by a complex repertoire of factors that precisely regulate the activation, proliferation, differentiation, and integration of the newborn cells. A growing number of studies also report low-level neurogenesis in regions of the adult brain outside these established neurogenic niches-potentially via NSC recruitment or activation of local, quiescent NSCs-under perturbations such as ischemia, cell death, or viral gene delivery of proneural growth factors. We have explored whether implantation of engineered biomaterials can stimulate neurogenesis in normally quiescent regions of the brain. Specifically, recombinant versions of factors found within the NSC microenvironment, Sonic hedgehog, and ephrin-B2 were conjugated to long polymers, thereby creating highly bioactive, multivalent ligands that begin to emulate components of the neurogenic niche. In this engineered biomaterial microenvironment, new neuron formation was observed in normally non-neurogenic regions of the brain, the striatum, and the cortex, and combining these multivalent biomaterials with stromal cell-derived factor-1a increased neuronal commitment of newly divided cells seven-to eightfold in these regions. Additionally, the decreased hippocampal neurogenesis of geriatric rodents was partially rescued toward levels of young animals. We thus demonstrate for the first time de novo neurogenesis in both the cortex and striatum of adult rodents stimulated solely by delivery of synthetic biomaterial forms of proteins naturally found within adult neurogenic niches, offering the potential to replace neurons lost in neurodegenerative disease or injury as an alternative to cell implantation. STEM CELLS

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The effect of multivalent Sonic hedgehog on differentiation of human embryonic stem cells into dopaminergic and GABAergic neurons

Cited by 45 publications

References 40 publications

Multivalent Conjugates of Sonic Hedgehog Accelerate Diabetic Wound Healing

Multivalent Conjugates of Sonic Hedgehog Accelerate Diabetic Wound Healing

Neural patterning of human induced pluripotent stem cells in 3-D cultures for studying biomolecule-directed differential cellular responses

Biomaterial Microenvironments to Support the Generation of New Neurons in the Adult Brain

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