title: Hyaluronic acid-serum hydrogels rapidly restore metabolism of encapsulated stem cells and promote engraftment.
abstract: BACKGROUND
  Cell death due to anoikis, necrosis and cell egress from transplantation sites limits functional benefits of cellular cardiomyoplasty. Cell dissociation and suspension, which are a pre-requisite for most cell transplantation studies, lead to depression of cellular metabolism and anoikis, which contribute to low engraftment.
  
  
  OBJECTIVE
  We tissue engineered scaffolds with the goal of rapidly restoring metabolism, promoting viability, proliferation and engraftment of encapsulated stem cells.
  
  
  METHODS
  The carboxyl groups of HA were functionalized with N-hydroxysuccinimide (NHS) to yield HA succinimidyl succinate (HA-NHS) groups that react with free amine groups to form amide bonds. HA-NHS was cross-linked by serum to generate HA:Serum (HA:Ser) hydrogels. Physical properties of HA:Ser hydrogels were measured. Effect of encapsulating cardiosphere-derived cells (CDCs) in HA:Ser hydrogels on viability, proliferation, glucose uptake and metabolism was assessed in vitro. In vivo acute intra-myocardial cell retention of (18)FDG-labeled CDCs encapsulated in HA:Ser hydrogels was quantified. Effect of CDC encapsulation in HA:Ser hydrogels on in vivo metabolism and engraftment at 7 days was assessed by serial, dual isotope SPECT-CT and bioluminescence imaging of CDCs expressing the Na-iodide symporter and firefly luciferase genes respectively. Effect of HA:Ser hydrogels ± CDCs on cardiac function was assessed at 7 days & 28 days post-infarct.
  
  
  RESULTS
  HA:Ser hydrogels are highly bio-adhesive, biodegradable, promote rapid cell adhesion, glucose uptake and restore bioenergetics of encapsulated cells within 1 h of encapsulation, both in vitro and in vivo. These metabolic scaffolds can be applied epicardially as a patch to beating hearts or injected intramyocardially. HA:Ser hydrogels markedly increase acute intramyocardial retention (∼6 fold), promote in vivo viability, proliferation, engraftment of encapsulated stem cells and angiogenesis.
  
  
  CONCLUSIONS
  HA:Ser hydrogels serve as 'synthetic stem cell niches' that rapidly restore metabolism of encapsulated stem cells, promote stem cell engraftment and angiogenesis. These first ever, tissue engineered metabolic scaffolds hold promise for clinical translation in conjunction with CDCs and possibly other stem cell types.
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Angel T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Mehmet F
authors.initials: MF
authors.lastname: Karakas
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Styliani
authors.initials: S
authors.lastname: Vakrou
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Junaid
authors.initials: J
authors.lastname: Afzal
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rittenbach
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Wahl
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Steenbergen
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Benjamin M W
authors.initials: BM
authors.lastname: Tsui
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Elisseeff
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: M Roselle
authors.initials: MR
authors.lastname: Abraham
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D002448:Cell Adhesion; D049109:Cell Proliferation; D002470:Cell Survival; D017690:Cell Transplantation; D004452:Echocardiography; D055119:Elastic Modulus; D053595:Embryonic Stem Cells / Q000166:cytology; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D020100:Hydrogels / Q000737:chemistry*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D064847:Multimodal Imaging; D009206:Myocardium / Q000378:metabolism; D009389:Neovascularization, Pathologic; D051381:Rats; D011921:Rats, Inbred WKY; D033581:Stem Cell Transplantation / Q000295:instrumentation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology*; D023822:Tissue Engineering; D054457:Tissue Scaffolds; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D001672:Biocompatible Materials; D020100:Hydrogels; D036341:Intercellular Signaling Peptides and Proteins; D019788:Fluorodeoxyglucose F18; D006820:Hyaluronic Acid; D005947:Glucose
keywords: Angiogenesis; Engraftment; HA:Serum hydrogels; Metabolism; Molecular imaging; Stem cells