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

Research output: Contribution to journalArticle

40 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 languageEnglish
Article numbereaah5505
JournalScience Translational Medicine
Volume9
Issue number399
DOIs
Publication statusPublished - 2017 Jul 19

Fingerprint

Liver Diseases
Chronic Disease
Liver
Hepatocytes
Tissue Expansion
Hydrogel
Wounds and Injuries
Tissue Engineering
Stromal Cells
Cues
Endothelial Cells
Transplants
Growth
Proteins

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Stevens, K. R., Scull, M. A., Ramanan, V., Fortin, C. L., Chaturvedi, R. R., Knouse, K. A., ... 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
Stevens, Kelly R. ; Scull, Margaret A. ; Ramanan, Vyas ; Fortin, Chelsea L. ; Chaturvedi, Ritika R. ; Knouse, Kristin A. ; Xiao, Jing W. ; Fung, Canny ; Mirabella, Teodelinda ; Chen, Amanda X. ; McCue, Margaret G. ; Yang, Michael T. ; Fleming, Heather E. ; Chung, Kwanghun ; De Jong, Ype P. ; Chen, Christopher S. ; Rice, Charles M. ; Bhatia, Sangeeta N. / In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease. In: Science Translational Medicine. 2017 ; Vol. 9, No. 399.
@article{1bbb6ef9555146329911112f8e0bc36c,
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.}",
year = "2017",
month = "7",
day = "19",
doi = "10.1126/scitranslmed.aah5505",
language = "English",
volume = "9",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "399",

}

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

In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease. / Stevens, Kelly R.; Scull, Margaret A.; Ramanan, Vyas; Fortin, Chelsea L.; Chaturvedi, Ritika R.; Knouse, Kristin A.; Xiao, Jing W.; Fung, Canny; Mirabella, Teodelinda; Chen, Amanda X.; McCue, Margaret G.; Yang, Michael T.; Fleming, Heather E.; Chung, Kwanghun; De Jong, Ype P.; Chen, Christopher S.; Rice, Charles M.; Bhatia, Sangeeta N.

In: Science Translational Medicine, Vol. 9, No. 399, eaah5505, 19.07.2017.

Research output: Contribution to journalArticle

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85025444300&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85025444300&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aah5505

DO - 10.1126/scitranslmed.aah5505

M3 - Article

C2 - 28724577

AN - SCOPUS:85025444300

VL - 9

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 399

M1 - eaah5505

ER -