Head and Neck

A novel in vivo model for evaluating functional restoration of a tissue-engineered salivary gland

Swati Pradhan-Bhatt PhD

Department of Biological Sciences, Biomedical Engineering Program, University of Delaware, Newark, Delaware

Department of Materials Sciences and Engineering, Biomedical Engineering Program , University of Delaware, Newark, Delaware

Department of Otolaryngology–Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

Search for more papers by this author

Daniel A. Harrington PhD,

Daniel A. Harrington PhD

Department of Biochemistry and Cell Biology, Rice University, Houston, Texas

Search for more papers by this author

Randall L. Duncan PhD,

Randall L. Duncan PhD

Department of Biological Sciences, Biomedical Engineering Program, University of Delaware, Newark, Delaware

Department of Materials Sciences and Engineering, Biomedical Engineering Program , University of Delaware, Newark, Delaware

Department of Otolaryngology–Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

Search for more papers by this author

Mary C. Farach-Carson PhD,

Mary C. Farach-Carson PhD

Department of Biological Sciences, Biomedical Engineering Program, University of Delaware, Newark, Delaware

Department of Materials Sciences and Engineering, Biomedical Engineering Program , University of Delaware, Newark, Delaware

Helen F. Graham Cancer Center, Christiana Care, Newark, Delaware

Search for more papers by this author

Xinqiao Jia PhD,

Xinqiao Jia PhD

the Center for Translational Cancer Research, Biomedical Engineering Program, University of Delaware, Newark, Delaware

Department of Biochemistry and Cell Biology, Rice University, Houston, Texas

Search for more papers by this author

Robert L. Witt MD,

Corresponding Author

Robert L. Witt MD

Department of Biological Sciences, Biomedical Engineering Program, University of Delaware, Newark, Delaware

the Center for Translational Cancer Research, Biomedical Engineering Program, University of Delaware, Newark, Delaware

Helen F. Graham Cancer Center, Christiana Care, Newark, Delaware

Department of Otolaryngology–Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

Send correspondence to Robert L. Witt, MD, Helen F. Graham Cancer Center, Christiana Care, 4745 Ogletown-Stanton Road, MAP #1, Suite 112, Newark, DE 19713. E-mail: [email protected]Search for more papers by this author

Swati Pradhan-Bhatt PhD,

Swati Pradhan-Bhatt PhD

Department of Biological Sciences, Biomedical Engineering Program, University of Delaware, Newark, Delaware

Department of Materials Sciences and Engineering, Biomedical Engineering Program , University of Delaware, Newark, Delaware

Department of Otolaryngology–Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

Search for more papers by this author

Daniel A. Harrington PhD,

Daniel A. Harrington PhD

Department of Biochemistry and Cell Biology, Rice University, Houston, Texas

Search for more papers by this author

Randall L. Duncan PhD,

Randall L. Duncan PhD

Department of Biological Sciences, Biomedical Engineering Program, University of Delaware, Newark, Delaware

Department of Materials Sciences and Engineering, Biomedical Engineering Program , University of Delaware, Newark, Delaware

Department of Otolaryngology–Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

Search for more papers by this author

Mary C. Farach-Carson PhD,

Mary C. Farach-Carson PhD

Department of Biological Sciences, Biomedical Engineering Program, University of Delaware, Newark, Delaware

Department of Materials Sciences and Engineering, Biomedical Engineering Program , University of Delaware, Newark, Delaware

Helen F. Graham Cancer Center, Christiana Care, Newark, Delaware

Search for more papers by this author

Xinqiao Jia PhD,

Xinqiao Jia PhD

the Center for Translational Cancer Research, Biomedical Engineering Program, University of Delaware, Newark, Delaware

Department of Biochemistry and Cell Biology, Rice University, Houston, Texas

Search for more papers by this author

Robert L. Witt MD,

Corresponding Author

Robert L. Witt MD

Department of Biological Sciences, Biomedical Engineering Program, University of Delaware, Newark, Delaware

the Center for Translational Cancer Research, Biomedical Engineering Program, University of Delaware, Newark, Delaware

Helen F. Graham Cancer Center, Christiana Care, Newark, Delaware

Department of Otolaryngology–Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

First published: 06 July 2013

https://doi.org/10.1002/lary.24297

Citations: 45

Presented at the Triological Society 116th Annual Meeting at COSM, Orlando, Florida, U.S.A., April 10–14, 2013.

This work was supported by a private philanthropic contribution, and NIH/DE R01 DE022386, NIH/NCI P01-CA098912, and COBRE P20-RR016458 grants.

The authors have no other funding, financial relationships, or conflicts of interest to disclose.

Share a link

Email
Wechat
Bluesky

Abstract

Objectives/Hypothesis

To create a novel model for development of a tissue-engineered salivary gland from human salivary gland cells that retains progenitor cell markers useful for treatment of radiation-induced xerostomia.

Study Design

A three-dimensional (3D) hyaluronic acid (HA)-based hydrogel scaffold was used to encapsulate primary human salivary gland cells and to obtain organized acini-like spheroids. Hydrogels were implanted into rat models, and cell viability and receptor expression were evaluated.

Methods

A parotid gland surgical resection model for xenografting was developed. Salivary cells loaded in HA hydrogels formed spheroids and in vitro were implanted in the three-fourths resected parotid bed of athymic rats. Implants were removed after 1 week and analyzed for spheroid viability and phenotype retention.

Results

Spheroids in 3D stained positive for HA receptors CD168/RHAMM and CD44, which is also a progenitor cell marker. The parotid gland three-fourths resection model was well-tolerated by rodent hosts, and the salivary cell/hydrogel scaffolds were adherent to the remaining parotid gland, with no obvious signs of inflammation. A majority of human cells in the extracted hydrogels demonstrated robust expression of CD44.

Conclusions

A 3D HA-based hydrogel scaffold that supported long-term culture of salivary gland cells into organized spheroids was established. An in vivo salivary gland resection model was developed that allowed for integration of the 3D HA hydrogel scaffold with the existing glandular parenchyma. The expression of CD44 among salivary cultures may partially explain their regenerative potential, and the expression of CD168/RHAMM along with CD44 may aid the development of these 3D spheroids into regenerated salivary glands

Level of Evidence

NA Laryngoscope, 124:456–461, 2014

BIBLIOGRAPHY

1Macchiarini P, Jungebluth P, Go T, et al. Clinical transplantation of a tissue-engineered airway. Lancet 2008; 372: 2023–2030.
10.1016/S0140-6736(08)61598-6
PubMed Web of Science® Google Scholar
2Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet 2006; 367: 1241–1246.
10.1016/S0140-6736(06)68438-9
PubMed Web of Science® Google Scholar
3Pradhan-Bhatt S, Harrington DA, Duncan RL, Jia X, Witt RL, Farach-Carson MCP. Implantable three-dimensional salivary spheroid assemblies demonstrate fluid and protein secretory responses to neurotransmitters. Tissue Eng Part A 2013; 19: 1610–1620.
10.1089/ten.tea.2012.0301
CAS PubMed Web of Science® Google Scholar
4Pradhan S, Liu C, Zhang C, Jia X, Farach-Carson MC, Witt RL. Lumen formation in 3D cultures of salivary acinar cells. Otolaryngol Head Neck Surg 2010; 142: 191–195.
10.1016/j.otohns.2009.10.039
PubMed Web of Science® Google Scholar
5Pradhan S, Zhang C, Jia X, Carson DD, Witt R, Farach-Carson MC. Perlecan domain IV peptide stimulates salivary gland cell assembly in vitro. Tissue Eng Part A 2009; 15: 3309–3320.
10.1089/ten.tea.2008.0669
CAS PubMed Web of Science® Google Scholar
6Xu X, Jha AK, Harrington DA, Farach-Carson MC, Jia X. Hyaluronic acid-based hydrogels: from a natural polysaccharide to complex networks. Soft Matter 2012; 8: 3280–3294.
10.1039/c2sm06463d
CAS PubMed Web of Science® Google Scholar
7Fonseca I, Moura Nunes JF, Soares J. Expression of CD44 isoforms in normal salivary gland tissue: an immunohistochemical and ultrastructural study. Histochem Cell Biol 2000; 114: 483–488.
CAS PubMed Web of Science® Google Scholar
8Maria OM, Maria AM, Cai Y, Tran SD. Cell surface markers CD44 and CD166 localized specific populations of salivary acinar cells. Oral Dis 2012; 18: 162–168.
10.1111/j.1601-0825.2011.01858.x
CAS PubMed Web of Science® Google Scholar
9Oliferenko S, Kaverina I, Small JV, Huber LA. Hyaluronic acid (HA) binding to CD44 activates Rac1 and induces lamellipodia outgrowth. J Cell Biol 2000; 148: 1159–1164.
10.1083/jcb.148.6.1159
CAS PubMed Web of Science® Google Scholar
10Tolg C, Hamilton SR, Turley EA. The role of the hyaluronan receptor RHAMM in wound repair and tumorigenesis. In: HG Garg, CA Hales, eds. Chemistry and Biology of Hyaluronan. Amsterdam, the Netherlands: Elsevier; 2004: 125–151.
10.1016/B978-008044382-9/50037-6
Google Scholar
11Herrera MB, Bussolati B, Bruno S, et al. Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney Int 2007; 72: 430–441.
10.1038/sj.ki.5002334
CAS PubMed Web of Science® Google Scholar
12Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 2003; 4: 33–45.
10.1038/nrm1004
CAS PubMed Web of Science® Google Scholar
13Maxwell CA, McCarthy J, Turley E. Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions? J Cell Sci 2008; 121: 925–932.
10.1242/jcs.022038
CAS PubMed Web of Science® Google Scholar
14Franzmann EJ, Reategui EP, Pedroso F, et al. Soluble CD44 is a potential marker for the early detection of head and neck cancer. Cancer Epidemiol Biomarkers Prev 2007; 16: 1348–1355.
10.1158/1055-9965.EPI-06-0011
CAS PubMed Web of Science® Google Scholar
15Groma V, Kazanceva A, Nora-Krukle Z, Murovska M. Oropharyngeal malignant epithelial cell, lymphocyte and macrophage CD44 surface receptors for hyaluronate are expressed in sustained EBV infection: immunohistochemical data and EBV DNA tissue indices. Pathol Res Pract 2012; 208: 518–526.
10.1016/j.prp.2012.05.017
CAS Web of Science® Google Scholar
16Shen S, Yang W, Wang Z, et al. Tumor-initiating cells are enriched in CD44(hi) population in murine salivary gland tumor. PloS One 2011; 6: e23282.
10.1371/journal.pone.0023282
CAS Web of Science® Google Scholar

Citing Literature

Volume124, Issue2

February 2014

Pages 456-461

A novel in vivo model for evaluating functional restoration of a tissue-engineered salivary gland

Abstract

Objectives/Hypothesis

Study Design

Methods

Results

Conclusions

Level of Evidence

BIBLIOGRAPHY

Citing Literature

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

A novel in vivo model for evaluating functional restoration of a tissue-engineered salivary gland

Abstract

Objectives/Hypothesis

Study Design

Methods

Results

Conclusions

Level of Evidence

BIBLIOGRAPHY

Citing Literature

References

Related

Information