Holger Willenbring, MD, PhD

Professor
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
Department of Surgery

Unlike other vertebrates, adult mammals have limited organ regeneration capabilities. A notable exception is the liver. Hepatocytes, the cells of the liver that provide its characteristic functions, are normally mitotically inactive, but, in contrast to other differentiated cells such as cardiomyocytes or neurons, have retained the ability to divide upon tissue loss or damage. A hepatocyte can divide more than 100 times and this ability is maintained in its progeny so that a single cell could theoretically be used to regenerate an entire liver. We are investigating the molecular mechanisms underlying hepatocyte regeneration with the goal of unlocking the regenerative capabilities of other differentiated cell types. 

In chronic liver diseases the stem cell-like proliferative capabilities of hepatocytes are exhausted or suppressed to prevent malignant transformation of damaged cells. Hepatocyte cell-cycle arrest stimulates the emergence and expansion of liver progenitor cells, which can give rise to hepatocytes and cholangiocytes, the cells that line the bile ducts. Liver progenitor cells are thought to derive from liver stem cells residing in bile ducts. However, whether liver stem cells are bona fide stem cells set aside during development, or dedifferentiated cholangiocytes, remains to be determined. We are using lineage tracing to identify and isolate the adult liver stem cell with the goal of understanding how proliferation and differentiation of this cell are regulated. These analyses inform our efforts to generate therapeutically effective surrogate hepatocytes either by directed differentiation of embryonic stem cells or induced pluripotent stem cells, or by direct reprogramming of somatic cells. 

The staggered regenerative processes in the adult liver have obscured the identity of the cell of origin of liver cancer. The previously prevailing paradigm was that liver cancers originate from damaged hepatocytes undergoing dedifferentiation. However, recent evidence suggests a liver progenitor cell origin of some liver cancers. Progenitor cell characteristics could explain why liver cancer is refractory to currently available therapies. We are using our ability to follow the fate of liver progenitor cells or differentiated hepatocytes to identify and isolate the cell that gives rise to liver cancer. Our goal is to determine the molecular mechanisms involved in liver cancer initiation and recurrence, which we hope will enable new strategies for early detection and effective eradication.

Research Summary: 
Mechanisms of Liver Regeneration and Cancer

Websites

Publications: 

Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages.

Nature communications

Groeger M, Matsuo K, Heidary Arash E, Pereira A, Le Guillou D, Pino C, Telles-Silva KA, Maher JJ, Hsiao EC, Willenbring H

Human iPSC-Derived Proinflammatory Macrophages cause Insulin Resistance in an Isogenic White Adipose Tissue Microphysiological System.

Small (Weinheim an der Bergstrasse, Germany)

Qi L, Matsuo K, Pereira A, Lee YT, Zhong F, He Y, Zushin PH, Gr?ger M, Sharma A, Willenbring H, Hsiao EC, Stahl A

Reply to "The Role of Aquaporin 9 in Modeling of Ornithine Transcarbamylase Deficiency".

Hepatology (Baltimore, Md.)

Laemmle A, Häberle J, Willenbring H

Aquaporin 9 Induction in Human iPSC-derived Hepatocytes Facilitates Modeling of Ornithine Transcarbamylase Deficiency.

Hepatology (Baltimore, Md.)

Laemmle A, Poms M, Hsu B, Borsuk M, Rüfenacht V, Robinson J, Sadowski MC, Nuoffer JM, Häberle J, Willenbring H

Integrated Isogenic Human Induced Pluripotent Stem Cell-Based Liver and Heart Microphysiological Systems Predict Unsafe Drug-Drug Interaction.

Frontiers in pharmacology

Lee-Montiel FT, Laemmle A, Charwat V, Dumont L, Lee CS, Huebsch N, Okochi H, Hancock MJ, Siemons B, Boggess SC, Goswami I, Miller EW, Willenbring H, Healy KE

iPSC-derived hepatocytes from patients with nonalcoholic fatty liver disease display a disease-specific gene expression profile.

Gastroenterology

Duwaerts CC, Le Guillou D, Her CL, Phillips NJ, Willenbring H, Mattis AN, Maher JJ

Transcriptomic traces of adult human liver progenitor cells.

Hepatology (Baltimore, Md.)

Kurial SNT, Willenbring H

Broad Distribution of Hepatocyte Proliferation in Liver Homeostasis and Regeneration.

Cell stem cell

Chen F, Jimenez RJ, Sharma K, Luu HY, Hsu BY, Ravindranathan A, Stohr BA, Willenbring H

Hepatocyte Nuclear Factor 4 alpha (HNF4a) Activation is Essential for Termination of Liver Regeneration.

Hepatology (Baltimore, Md.)

Huck I, Gunewardena S, Espanol-Suner R, Willenbring H, Apte U

De novo formation of the biliary system by TGFß-mediated hepatocyte transdifferentiation.

Nature

Schaub JR, Huppert KA, Kurial SNT, Hsu BY, Cast AE, Donnelly B, Karns RA, Chen F, Rezvani M, Luu HY, Mattis AN, Rougemont AL, Rosenthal P, Huppert SS, Willenbring H

Postnatal Organogenesis by Transdifferentiation.

The FASEB Journal

Holger Willenbring

Advances in cholangiocarcinoma research: report from the third Cholangiocarcinoma Foundation Annual Conference.

Journal of gastrointestinal oncology

Abou-Alfa GK, Andersen JB, Chapman W, Choti M, Forbes SJ, Gores GJ, Hong TS, Harding JJ, Vander Heiden MG, Javle M, Kelley RK, Kwong LN, Lowery M, Merrell A, Miyabe K, Rhim A, Saha S, Sia D, Tanasanvimon S, Venook A, Valle JW, Walesky C, Whetstine J, Willenbring H, Zhu AX, Mayer D, Stanger BZ

In Vivo Hepatic Reprogramming of Myofibroblasts with AAV Vectors as a Therapeutic Strategy for Liver Fibrosis.

Cell stem cell

Rezvani M, Español-Suñer R, Malato Y, Dumont L, Grimm AA, Kienle E, Bindman JG, Wiedtke E, Hsu BY, Naqvi SJ, Schwabe RF, Corvera CU, Grimm D, Willenbring H

Assessing the therapeutic potential of lab-made hepatocytes.

Hepatology (Baltimore, Md.)

Rezvani M, Grimm AA, Willenbring H

Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha.

Hepatology (Baltimore, Md.)

Desai SS, Tung JC, Zhou VX, Grenert JP, Malato Y, Rezvani M, Español-Suñer R, Willenbring H, Weaver VM, Chang TT

A screen in mice uncovers repression of lipoprotein lipase by microRNA-29a as a mechanism for lipid distribution away from the liver.

Hepatology (Baltimore, Md.)

Mattis AN, Song G, Hitchner K, Kim RY, Lee AY, Sharma AD, Malato Y, McManus MT, Esau CC, Koller E, Koliwad S, Lim LP, Maher JJ, Raffai RL, Willenbring H

AAV8-mediated in vivo overexpression of miR-155 enhances the protective capacity of genetically attenuated malarial parasites.

Molecular therapy : the journal of the American Society of Gene Therapy

Hentzschel F, Hammerschmidt-Kamper C, Börner K, Heiss K, Knapp B, Sattler JM, Kaderali L, Castoldi M, Bindman JG, Malato Y, Willenbring H, Mueller AK, Grimm D

Brief report: Parthenogenetic embryonic stem cells are an effective cell source for therapeutic liver repopulation.

Stem cells (Dayton, Ohio)

Espejel S, Eckardt S, Harbell J, Roll GR, McLaughlin KJ, Willenbring H

Inhibition of microRNA-24 expression in liver prevents hepatic lipid accumulation and hyperlipidemia.

Hepatology (Baltimore, Md.)

Ng R, Wu H, Xiao H, Chen X, Willenbring H, Steer CJ, Song G

Mouse liver repopulation with hepatocytes generated from human fibroblasts.

Nature

Zhu S, Rezvani M, Harbell J, Mattis AN, Wolfe AR, Benet LZ, Willenbring H, Ding S

Human induced pluripotent stem cell-based microphysiological tissue models of myocardium and liver for drug development.

Stem cell research & therapy

Mathur A, Loskill P, Hong S, Lee J, Marcus SG, Dumont L, Conklin BR, Willenbring H, Lee LP, Healy KE

MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer.

Hepatology (Baltimore, Md.)

Lim L, Balakrishnan A, Huskey N, Jones KD, Jodari M, Ng R, Song G, Riordan J, Anderton B, Cheung ST, Willenbring H, Dupuy A, Chen X, Brown D, Chang AN, Goga A

Transplantable liver organoids made from only three ingredients.

Cell stem cell

Willenbring H, Soto-Gutierrez A

Highly efficient differentiation of functional hepatocytes from human induced pluripotent stem cells.

Stem cells translational medicine

Ma X, Duan Y, Tschudy-Seney B, Roll G, Behbahan IS, Ahuja TP, Tolstikov V, Wang C, McGee J, Khoobyari S, Nolta JA, Willenbring H, Zern MA

Cholangiocarcinomas can originate from hepatocytes in mice.

The Journal of clinical investigation

Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N, Ribback S, Gores GJ, Dombrowski F, Evert M, Chen X, Willenbring H

A ZFN/piggyBac step closer to autologous liver cell therapy.

Hepatology (Baltimore, Md.)

Mattis AN, Willenbring H

A microRNA-21 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration.

The Journal of clinical investigation

Ng R, Song G, Roll GR, Frandsen NM, Willenbring H

Stem cells in liver diseases and cancer: recent advances on the path to new therapies.

Hepatology (Baltimore, Md.)

Rountree CB, Mishra L, Willenbring H

Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration.

The Journal of clinical investigation

Malato Y, Naqvi S, Schürmann N, Ng R, Wang B, Zape J, Kay MA, Grimm D, Willenbring H

Core promoter recognition complex changes accompany liver development.

Proceedings of the National Academy of Sciences of the United States of America

D'Alessio JA, Ng R, Willenbring H, Tjian R

The MAP3K TAK1: a chock block to liver cancer formation.

Hepatology (Baltimore, Md.)

Malato Y, Willenbring H

Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice.

The Journal of clinical investigation

Espejel S, Roll GR, McLaughlin KJ, Lee AY, Zhang JY, Laird DJ, Okita K, Yamanaka S, Willenbring H

miRNAs regulate SIRT1 expression during mouse embryonic stem cell differentiation and in adult mouse tissues.

Aging

Saunders LR, Sharma AD, Tawney J, Nakagawa M, Okita K, Yamanaka S, Willenbring H, Verdin E

Therapeutic liver reconstitution with murine cells isolated long after death.

Gastroenterology

Erker L, Azuma H, Lee AY, Guo C, Orloff S, Eaton L, Benedetti E, Jensen B, Finegold M, Willenbring H, Grompe M

MicroRNAs control hepatocyte proliferation during liver regeneration.

Hepatology (Baltimore, Md.)

Song G, Sharma AD, Roll GR, Ng R, Lee AY, Blelloch RH, Frandsen NM, Willenbring H

Loss of p21 permits carcinogenesis from chronically damaged liver and kidney epithelial cells despite unchecked apoptosis.

Cancer cell

Willenbring H, Sharma AD, Vogel A, Lee AY, Rothfuss A, Wang Z, Finegold M, Grompe M

On the origin of the term "stem cell".

Cell stem cell

Ramalho-Santos M, Willenbring H

Myeloid lineage progenitors give rise to vascular endothelium.

Proceedings of the National Academy of Sciences of the United States of America

Bailey AS, Willenbring H, Jiang S, Anderson DA, Schroeder DA, Wong MH, Grompe M, Fleming WH

Bone marrow-derived cells fuse with normal and transformed intestinal stem cells.

Proceedings of the National Academy of Sciences of the United States of America

Rizvi AZ, Swain JR, Davies PS, Bailey AS, Decker AD, Willenbring H, Grompe M, Fleming WH, Wong MH

Sustained phosphorylation of Bid is a marker for resistance to Fas-induced apoptosis during chronic liver diseases.

Gastroenterology

Vogel A, Aslan JE, Willenbring H, Klein C, Finegold M, Mount H, Thomas G, Grompe M

Myeloid Lineage-Restricted Progenitors Contribute to Vascular Endothelium.

Blood

Alexis S. Bailey, Holger Willenbring, Shuguang Jiang, David A. Schroeder, Daniel A. Anderson, Markus Grompe, Melissa H. Wong, William H. Fleming

In vivo genetic selection of renal proximal tubules.

Molecular therapy : the journal of the American Society of Gene Therapy

Held PK, Al-Dhalimy M, Willenbring H, Akkari Y, Jiang S, Torimaru Y, Olson S, Fleming WH, Finegold M, Grompe M

Therapeutic cell fusion.

The British journal of surgery

Willenbring H

Delineating the hepatocyte's hematopoietic fusion partner.

Cell cycle (Georgetown, Tex.)

Willenbring H, Grompe M

Myelomonocytic cells are sufficient for therapeutic cell fusion in liver.

Nature medicine

Willenbring H, Bailey AS, Foster M, Akkari Y, Dorrell C, Olson S, Finegold M, Fleming WH, Grompe M

Embryonic versus adult stem cell pluripotency: in liver only fusion matters.

Journal of assisted reproduction and genetics

Willenbring H, Grompe M

Cell fusion is the principal source of bone-marrow-derived hepatocytes.

Nature

Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Olson S, Grompe M

Genomic structure and transcript variants of the human methylenetetrahydrofolate reductase gene.

European journal of human genetics : EJHG

Homberger A, Linnebank M, Winter C, Willenbring H, Marquardt T, Harms E, Koch HG

Telomerase activity distinguishes between neuroblastomas with good and poor prognosis.

Annals of oncology : official journal of the European Society for Medical Oncology

Poremba C, Willenbring H, Hero B, Christiansen H, Schäfer KL, Brinkschmidt C, Jürgens H, Böcker W, Dockhorn-Dworniczak B

Telomerase activity in human proliferative breast lesions.

International journal of oncology

Poremba C, Böcker W, Willenbring H, Schäfer KL, Otterbach F, Bürger H, Diallo R, Dockhorn-Dworniczak B

Nonisotopic single strand conformation analysis of the 5 alpha-reductase type 2 gene for the diagnosis of 5 alpha-reductase deficiency.

The Journal of clinical endocrinology and metabolism

Hiort O, Sinnecker GH, Willenbring H, Lehners A, Zöllner A, Struve D

Molecular genetic analysis and human chorionic gonadotropin stimulation tests in the diagnosis of prepubertal patients with partial 5 alpha-reductase deficiency.

European journal of pediatrics

Hiort O, Willenbring H, Albers N, Hecker W, Engert J, Dibbelt L, Sinnecker GH