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THE STEM CELL NICHE

Nuclear Magnetic Resonance Metabolomic Footprinting of Human Hepatic Stem Cells and Hepatoblasts Cultured in Hyaluronan-Matrix Hydrogels

Departments of ^aCell and Molecular Physiology and
^bBiomedical Engineering,
^cProgram in Molecular Biology and Biotechnology, and
^dCancer Center and Center for Gastrointestinal and Biliary Disease Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA;
^eDepartment of Medicinal Chemistry, Center for Therapeutic Biomaterials, Salt Lake City, Utah, USA

Key Words. Nuclear magnetic resonance • Metabolomics • Footprinting • Human • Hepatic stem cells • Hepatoblasts • Extracellular matrix • Hyaluronans • Collagens

Correspondence: William S. Turner, Ph.D., University of North Carolina School of Medicine, Campus Box 7038, Glaxo Building, Rooms 32-35, Chapel Hill, North Carolina 27599, USA. Telephone: 919-966-0347; Fax: 919-6112; e-mail: wsturner{at}email.unc.edu; or Lola M. Reid, Ph.D., University of North Carolina School of Medicine, Campus Box 7038, Glaxo Building, Rooms 32–35, Chapel Hill, North Carolina 27599, USA. Telephone: 919-966-0347; Fax: 919-6112; e-mail: lmreid{at}email.unc.edu

Received October 19, 2007; accepted for publication January 30, 2008.
First published online in STEM CELLS EXPRESS   March 6, 2008.



Human hepatoblasts (hHBs) and human hepatic stem cells (hHpSCs) were maintained in serum-free Kubota's medium, a defined medium tailored for hepatic progenitors, and on culture plastic versus hyaluronan hydrogels mixed with specific combinations of extracellular matrix components (e.g., type I collagen and laminin). Nuclear magnetic resonance spectroscopy was used to define metabolomic profiles for each substratum tested. The hHpSCs on culture plastic survived throughout the culture study, whereas hHBs on plastic died within 7–10 days. Both survived and expanded in all hydrogel-matrix combinations tested for more than 4 weeks. Profiles of hundreds of metabolites were narrowed to a detailed analysis of eight, such as glucose, lactate, and glutamine, shown to be significant components of cellular pathways, including the Krebs and urea cycles. The metabolomic profiles indicated that hHpSCs on plastic remained as stem cells expressing low levels of albumin but no -fetoprotein (AFP); those in hydrogels were primarily hHBs, expressing AFP, albumin, and urea. Both hHpSCs and hHBs used energy provided by anaerobic metabolism. Variations in hyaluronan-matrix chemistry resulted in distinct profiles correlating with growth or with differentiative responses. Metabolomic footprinting offers noninvasive and nondestructive assessment of physiological states of stem/progenitor cells ex vivo.

Disclosure of potential conflicts of interest is found at the end of this article.