In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease

Kelly R. Stevens; Margaret A. Scull; Vyas Ramanan; Chelsea L. Fortin; Ritika R. Chaturvedi; Kristin A. Knouse; Jing W. Xiao; Canny Fung; Teodelinda Mirabella; Amanda X. Chen; Margaret G. McCue; Michael T. Yang; Heather E. Fleming; Kwanghun Chung; Ype P. De Jong; Christopher S. Chen; Charles M. Rice; Sangeeta N. Bhatia

doi:10.1126/scitranslmed.aah5505

In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease

Kelly R. Stevens, Margaret A. Scull, Vyas Ramanan, Chelsea L. Fortin, Ritika R. Chaturvedi, Kristin A. Knouse, Jing W. Xiao, Canny Fung, Teodelinda Mirabella, Amanda X. Chen, Margaret G. McCue, Michael T. Yang, Heather E. Fleming, Kwanghun Chung, Ype P. De Jong, Christopher S. Chen, Charles M. Rice, Sangeeta N. Bhatia

Yonsei Advanced Science Institute

Research output: Contribution to journal › Article › peer-review

116 Citations (Scopus)

Abstract

Control of both tissue architecture and scale is a fundamental translational roadblock in tissue engineering. An experimental framework that enables investigation into how architecture and scaling may be coupled is needed. We fabricated a structurally organized engineered tissue unit that expanded in response to regenerative cues after implantation into mice with liver injury. Specifically, we found that tissues containing patterned human primary hepatocytes, endothelial cells, and stromal cells in a degradable hydrogel expanded more than 50-fold over the course of 11 weeks in mice with injured livers. There was a concomitant increase in graft function as indicated by the production of multiple human liver proteins. Histologically, we observed the emergence of characteristic liver stereotypical microstructures mediated by coordinated growth of hepatocytes in close juxtaposition with a perfused vasculature. We demonstrated the utility of this system for probing the impact of multicellular geometric architecture on tissue expansion in response to liver injury. This approach is a hybrid strategy that harnesses both biology and engineering to more efficiently deploy a limited cell mass after implantation.

Original language	English
Article number	eaah5505
Journal	Science Translational Medicine
Volume	9
Issue number	399
DOIs	https://doi.org/10.1126/scitranslmed.aah5505
Publication status	Published - 2017 Jul 19

Bibliographical note

Funding Information:
We thank A. Sappington for help with bioinformatics analysis, L. Wilson of Yecuris for advice regarding animal care, the Koch Institute BioMicroCenter for help with library sequencing, and the Swanson Biotechnology Center Microscopy Core for help with imaging. Funding: This study was supported by grants from the NIH (R01EB008396, R01DK85713, EB00262, U24DK059635, and P30-CA14051), the Skolkovo Institute of Science and Technology (022423-003), and the National Institute of Environmental Health Sciences (P30-ES002109). M.A.S. was supported by the National Research Service Award (F32AI091207), and K.A.K. was supported by the National Institute of General Medical Sciences Training Grant (T32GM007753). S.N.B. is a Howard Hughes Medical Institute investigator. Author contributions: K.R.S., M.A.S., V.R., C.L.F., R.R.C., K.A.K., J.W.X., C.F., T.M., A.X.C., M.G.M., M.T.Y., Y.P.d.J., and H.E.F. designed and performed all experiments. M.A.S., M.T.Y., Y.P.d.J., R.R.C., J.W.X., C.F., T.M., and C.L.F. designed and performed the transplant experiments. V.R. designed and analyzed the transcriptome experiments. K.A.K. designed and performed the partial hepatectomy experiments. M.G.M. and K.C. designed and performed the lectin analysis experiments. K.R.S., H.E.F., C.S.C., C.M.R., and S.N.B. wrote the paper. K.C., Y.P.d.J., C.S.C., C.M.R., and S.N.B. provided funding, contributed to experiment planning, and provided overall oversight of the study. Competing interests: S.N.B. is a co-founder of Hepregen. C.S.C. is co-founder of Innolign Biomedical. K.R.S., C.S.C., and S.N.B. are co-inventors on a patent entitled "SEEDs (in situ expansion of engineered devices) for templated regeneration" (#PCT/US2016/055972).

Publisher Copyright:
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.

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Medicine(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/scitranslmed.aah5505

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Stevens, K. R., Scull, M. A., Ramanan, V., Fortin, C. L., Chaturvedi, R. R., Knouse, K. A., Xiao, J. W., Fung, C., Mirabella, T., Chen, A. X., McCue, M. G., Yang, M. T., Fleming, H. E., Chung, K., De Jong, Y. P., Chen, C. S., Rice, C. M., & Bhatia, S. N. (2017). In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease. Science Translational Medicine, 9(399), [eaah5505]. https://doi.org/10.1126/scitranslmed.aah5505

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title = "In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease",

abstract = "Control of both tissue architecture and scale is a fundamental translational roadblock in tissue engineering. An experimental framework that enables investigation into how architecture and scaling may be coupled is needed. We fabricated a structurally organized engineered tissue unit that expanded in response to regenerative cues after implantation into mice with liver injury. Specifically, we found that tissues containing patterned human primary hepatocytes, endothelial cells, and stromal cells in a degradable hydrogel expanded more than 50-fold over the course of 11 weeks in mice with injured livers. There was a concomitant increase in graft function as indicated by the production of multiple human liver proteins. Histologically, we observed the emergence of characteristic liver stereotypical microstructures mediated by coordinated growth of hepatocytes in close juxtaposition with a perfused vasculature. We demonstrated the utility of this system for probing the impact of multicellular geometric architecture on tissue expansion in response to liver injury. This approach is a hybrid strategy that harnesses both biology and engineering to more efficiently deploy a limited cell mass after implantation.",

author = "Stevens, {Kelly R.} and Scull, {Margaret A.} and Vyas Ramanan and Fortin, {Chelsea L.} and Chaturvedi, {Ritika R.} and Knouse, {Kristin A.} and Xiao, {Jing W.} and Canny Fung and Teodelinda Mirabella and Chen, {Amanda X.} and McCue, {Margaret G.} and Yang, {Michael T.} and Fleming, {Heather E.} and Kwanghun Chung and {De Jong}, {Ype P.} and Chen, {Christopher S.} and Rice, {Charles M.} and Bhatia, {Sangeeta N.}",

note = "Funding Information: We thank A. Sappington for help with bioinformatics analysis, L. Wilson of Yecuris for advice regarding animal care, the Koch Institute BioMicroCenter for help with library sequencing, and the Swanson Biotechnology Center Microscopy Core for help with imaging. Funding: This study was supported by grants from the NIH (R01EB008396, R01DK85713, EB00262, U24DK059635, and P30-CA14051), the Skolkovo Institute of Science and Technology (022423-003), and the National Institute of Environmental Health Sciences (P30-ES002109). M.A.S. was supported by the National Research Service Award (F32AI091207), and K.A.K. was supported by the National Institute of General Medical Sciences Training Grant (T32GM007753). S.N.B. is a Howard Hughes Medical Institute investigator. Author contributions: K.R.S., M.A.S., V.R., C.L.F., R.R.C., K.A.K., J.W.X., C.F., T.M., A.X.C., M.G.M., M.T.Y., Y.P.d.J., and H.E.F. designed and performed all experiments. M.A.S., M.T.Y., Y.P.d.J., R.R.C., J.W.X., C.F., T.M., and C.L.F. designed and performed the transplant experiments. V.R. designed and analyzed the transcriptome experiments. K.A.K. designed and performed the partial hepatectomy experiments. M.G.M. and K.C. designed and performed the lectin analysis experiments. K.R.S., H.E.F., C.S.C., C.M.R., and S.N.B. wrote the paper. K.C., Y.P.d.J., C.S.C., C.M.R., and S.N.B. provided funding, contributed to experiment planning, and provided overall oversight of the study. Competing interests: S.N.B. is a co-founder of Hepregen. C.S.C. is co-founder of Innolign Biomedical. K.R.S., C.S.C., and S.N.B. are co-inventors on a patent entitled {"}SEEDs (in situ expansion of engineered devices) for templated regeneration{"} (#PCT/US2016/055972). Publisher Copyright: Copyright {\textcopyright} 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.",

year = "2017",

month = jul,

day = "19",

doi = "10.1126/scitranslmed.aah5505",

language = "English",

volume = "9",

journal = "Science Translational Medicine",

issn = "1946-6234",

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Stevens, KR, Scull, MA, Ramanan, V, Fortin, CL, Chaturvedi, RR, Knouse, KA, Xiao, JW, Fung, C, Mirabella, T, Chen, AX, McCue, MG, Yang, MT, Fleming, HE, Chung, K, De Jong, YP, Chen, CS, Rice, CM & Bhatia, SN 2017, 'In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease', Science Translational Medicine, vol. 9, no. 399, eaah5505. https://doi.org/10.1126/scitranslmed.aah5505

TY - JOUR

T1 - In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease

AU - Stevens, Kelly R.

AU - Scull, Margaret A.

AU - Ramanan, Vyas

AU - Fortin, Chelsea L.

AU - Chaturvedi, Ritika R.

AU - Knouse, Kristin A.

AU - Xiao, Jing W.

AU - Fung, Canny

AU - Mirabella, Teodelinda

AU - Chen, Amanda X.

AU - McCue, Margaret G.

AU - Yang, Michael T.

AU - Fleming, Heather E.

AU - Chung, Kwanghun

AU - De Jong, Ype P.

AU - Chen, Christopher S.

AU - Rice, Charles M.

AU - Bhatia, Sangeeta N.

N1 - Funding Information: We thank A. Sappington for help with bioinformatics analysis, L. Wilson of Yecuris for advice regarding animal care, the Koch Institute BioMicroCenter for help with library sequencing, and the Swanson Biotechnology Center Microscopy Core for help with imaging. Funding: This study was supported by grants from the NIH (R01EB008396, R01DK85713, EB00262, U24DK059635, and P30-CA14051), the Skolkovo Institute of Science and Technology (022423-003), and the National Institute of Environmental Health Sciences (P30-ES002109). M.A.S. was supported by the National Research Service Award (F32AI091207), and K.A.K. was supported by the National Institute of General Medical Sciences Training Grant (T32GM007753). S.N.B. is a Howard Hughes Medical Institute investigator. Author contributions: K.R.S., M.A.S., V.R., C.L.F., R.R.C., K.A.K., J.W.X., C.F., T.M., A.X.C., M.G.M., M.T.Y., Y.P.d.J., and H.E.F. designed and performed all experiments. M.A.S., M.T.Y., Y.P.d.J., R.R.C., J.W.X., C.F., T.M., and C.L.F. designed and performed the transplant experiments. V.R. designed and analyzed the transcriptome experiments. K.A.K. designed and performed the partial hepatectomy experiments. M.G.M. and K.C. designed and performed the lectin analysis experiments. K.R.S., H.E.F., C.S.C., C.M.R., and S.N.B. wrote the paper. K.C., Y.P.d.J., C.S.C., C.M.R., and S.N.B. provided funding, contributed to experiment planning, and provided overall oversight of the study. Competing interests: S.N.B. is a co-founder of Hepregen. C.S.C. is co-founder of Innolign Biomedical. K.R.S., C.S.C., and S.N.B. are co-inventors on a patent entitled "SEEDs (in situ expansion of engineered devices) for templated regeneration" (#PCT/US2016/055972). Publisher Copyright: Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.

PY - 2017/7/19

Y1 - 2017/7/19

N2 - Control of both tissue architecture and scale is a fundamental translational roadblock in tissue engineering. An experimental framework that enables investigation into how architecture and scaling may be coupled is needed. We fabricated a structurally organized engineered tissue unit that expanded in response to regenerative cues after implantation into mice with liver injury. Specifically, we found that tissues containing patterned human primary hepatocytes, endothelial cells, and stromal cells in a degradable hydrogel expanded more than 50-fold over the course of 11 weeks in mice with injured livers. There was a concomitant increase in graft function as indicated by the production of multiple human liver proteins. Histologically, we observed the emergence of characteristic liver stereotypical microstructures mediated by coordinated growth of hepatocytes in close juxtaposition with a perfused vasculature. We demonstrated the utility of this system for probing the impact of multicellular geometric architecture on tissue expansion in response to liver injury. This approach is a hybrid strategy that harnesses both biology and engineering to more efficiently deploy a limited cell mass after implantation.

AB - Control of both tissue architecture and scale is a fundamental translational roadblock in tissue engineering. An experimental framework that enables investigation into how architecture and scaling may be coupled is needed. We fabricated a structurally organized engineered tissue unit that expanded in response to regenerative cues after implantation into mice with liver injury. Specifically, we found that tissues containing patterned human primary hepatocytes, endothelial cells, and stromal cells in a degradable hydrogel expanded more than 50-fold over the course of 11 weeks in mice with injured livers. There was a concomitant increase in graft function as indicated by the production of multiple human liver proteins. Histologically, we observed the emergence of characteristic liver stereotypical microstructures mediated by coordinated growth of hepatocytes in close juxtaposition with a perfused vasculature. We demonstrated the utility of this system for probing the impact of multicellular geometric architecture on tissue expansion in response to liver injury. This approach is a hybrid strategy that harnesses both biology and engineering to more efficiently deploy a limited cell mass after implantation.

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In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

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