TY - JOUR
T1 - Hyaluronic acid-serum hydrogels rapidly restore metabolism of encapsulated stem cells and promote engraftment
AU - Chan, Angel T.
AU - Karakas, Mehmet F.
AU - Vakrou, Styliani
AU - Afzal, Junaid
AU - Rittenbach, Andrew
AU - Lin, Xiaoping
AU - Wahl, Richard L.
AU - Pomper, Martin G.
AU - Steenbergen, Charles J.
AU - Tsui, Benjamin M.W.
AU - Elisseeff, Jennifer H.
AU - Abraham, M. Roselle
N1 - Funding Information:
This work was funded by the American Heart Association (AHA-BGIA), NIH RO1 HL092985 and NIH UL1 RR 025005 (from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH). Dr. Angel Chan was supported by NIH T32HL07227 Training Grant. Dr. Mehmet F. Karakas was supported by a TUBITAK 2219 Research Programme Grant (Scientific and Technological Research Council of Turkey-TUBITAK) and Fulbright Grant (Bureau of Educational and Cultural Affairs, United States Department of State). We are grateful to James Fox, Jim Engles, Karen Fox-Talbot and Gilbert Green for technical assistance.
Publisher Copyright:
© 2015 Elsevier Ltd.
PY - 2015/12
Y1 - 2015/12
N2 - 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 18FDG-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. Conclusion: 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.
AB - 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 18FDG-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. Conclusion: 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.
KW - Angiogenesis
KW - Engraftment
KW - HA:Serum hydrogels
KW - Metabolism
KW - Molecular imaging
KW - Stem cells
UR - http://www.scopus.com/inward/record.url?scp=84943574830&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2015.09.001
DO - 10.1016/j.biomaterials.2015.09.001
M3 - Article
C2 - 26378976
AN - SCOPUS:84943574830
SN - 0142-9612
VL - 73
SP - 1
EP - 11
JO - Biomaterials
JF - Biomaterials
ER -