Lola M. Reid, PhD
Professor
Adjunct Professor in the Department of Biomolecular Engineering

Education:

University of North Carolina at Greensboro, 1963-65
University of Heidelberg, Germany, 1965-1966 (Junior Year Abroad)
BA, University of North Carolina at Chapel Hill, 1969
PhD, University of North Carolina at Chapel Hill, 1974
Postdoctoral Studies at the University of California at San Diego, La Jolla, California, 1974-1977 (Mentors: Dr. Gordon Sato and Dr. John Holland)

Research Themes

Two dynamically interacting sets of mechanisms govern tissue-specific gene expression and cell growth. 1) mechanisms in lineage biology regulate stem cells and their descendents, processes that define the repertoire of genes available to be regulated and 2) signal transduction mechanisms, induced by the synergistic effects of extracellular matrix components and soluble signals (hormones, growth factors), regulate the expression of the available genes. Studies in the lab focus on both classes of mechanisms in normal versus neoplastic tissue.

Liver Stem Cells and Lineage Biology

The acinus is the key structural and functional unit of the liver. In cross-section, it is organized like a wheel around two distinct vascular beds: six sets of portal triads, each with a portal venule, hepatic arteriole and a bile duct, form the periphery, and the central vein forms the hub. The parenchyma, effectively the "spokes" of the wheel, consist of plates of cells lined on both sides by the fenestrated sinusoidal endothelium (see Figure 1 and Table 1 below). By convention, the liver is demarcated into three zones: zone 1 is periportal (nearest to the portal venule); zone 2 is midacinar; and zone 3 is pericentral (nearest to the central vein). Based on their zonal location, hepatocytes display marked heterogeneity in morphology, gene expression, and biochemical function. Cell size increases from zone 1 to zone 3. Furthermore, in all mammalian systems, the hepatocytes in the adult liver show dramatic differences in DNA content from zone 1 to zone 3 changing from diploid in zone 1 to polyploid cells in zone 3. The extent of polyploidy is greatest in rodent systems with young adult rodent livers consisting of more than 90% polyploid cells. The small, diploid liver cells of zone 1 have greater capacity to proliferate than the polyploid cells of zones 2 and/or 3. , and that this capacity diminishes in cells of zone 2 and is largely absent in zone 3. Among the liver's diploid cells are a population of stem/progenitor cells that can be mobilized to proliferate extensively and to give rise to mature parenchymal cells. These cells are located in close proximity to the Canals of Hering that extend throughout zone 1 in rodents or even into portions of zone 2 in humans.

Figure 1.

Figure 2 Glutamine synthetase expression around central veins of rat livers (section and staining done by Dr. Huifei Lui)

Fluorescence-activated cell sorting (FACS) has been used to isolate populations of rat hepatic stem/progenitor cells from embryonic, neonatal and adult rat livers up to a year of age (Sigal et al, 1994, Sigal et al, 1995). More recently, hepatoblasts that were flow cytometrically-sorted by a defined antigenic profile were cultured under novel conditions permitting clonogenic expansion as demonstrated in Figure 3 (Kubota and Reid, 2000). The purified hepatoblasts are considerably smaller than hepatocytes (diameter about 10-12 m versus 20-50 m), and express alpha-fetoprotein (AFP), albumin and cytokeratin 19.

These hepatoblasts give rise to both mature hepatocytes and bile duct cells in vitro and in vivo. The expansion conditions consist of a serum-free medium with low calcium and no copper and then supplemented only with lipids, insulin and transferrin/Fe and embryonic stromal feeder cells, provided by STO feeder cells.

We have recently extended our studies of hepatic stem/progenitor cells to those derived from human livers. One of the stem cell populations identified is the bipotential hepatoblast, found to be similar to those from rat liver and found to have co-expression of albumin, alpha-fetoprotein and cytokeratin 19. The human cells form colonies at clonogenic seeding densities under the same conditions utilized for rodent hepatic progenitors (Figure 4). The antigenic profile of these cells and further characterization of them has been presented in detail in a manuscript by Moss N, Wauthier E, Bruce A, Furth M, and Reid LM (submitted).

	Figure 4. Colonies of hepatoblasts from human liver cultured in a serum-free, hormonally defined medium and on embryonic stromal feeders, STO cells (A) AFP expression. (B) Nomarski optics.

Signal Transduction Mechanisms Governed by Cooperative Effects of Extracellular Matrix and Soluble Signals

Transcriptional regulation of tissue-specific genes is dependent upon cooperative effects of hormones and plasma membrane-associated heparin proteoglycans, present in vivo in quiescent tissues and in cells ex vivo at high cell densities. Heparan sulfate proteoglycans associated with the plasma membranes in regenerating tissues and in cells ex vivo at low cell densities are inactive or inhibitory. A structure-function analysis of these proteoglycans has revealed that the ability to regulate transcription is associated with heparin saccharides with unique patterns of 0-sulfation. The heparin saccharides influence signal transduction pathways by modifying hormone or receptor conformation or stability, by regulating intracellular pH and ion channels, and by affects on intracellular trafficking of signals. Current studies are focused on developing rapid methods by which to isolate defined heparin saccharides to be able to characterize fully the biological responses and to be able to complete the process of identifying regulatory elements in tissue-specific genes regulated by complexes of the heparin saccharides and specific hormones.

Lola Reid was a professor in the Department of Molecular Pharmacology and in the Department of Immunology at the Albert Einstein College of Medicine, Bronx, New York, from 1977-1994. She moved to join the faculty at UNC in December, 1994. She has served on numerous editorial boards and grant study sections, has served as a consultant to many companies and for center grants at multiple institutions, and was a consultant to NASA on biological research in space. In 1995, she founded a company, Renaissance Cell Technologies, focused on clinical programs for liver cell therapies and commercial programs making use of liver lineage biology. The company was financed in 1997 by Incara Pharmaceuticals, Research Triangle Park, NC and in 2000 became a wholly owned subsidiary of Incara. In October, 2002, it was purchased by Toucan Capital, Bethesda, Maryland, to become an independent company, Vesta Therapeutics, dedicated to commercial and clinical programs leading to liver cell therapies and bioartificial organs.

Selected Publications:
(from more than 350 published, including more than 50 patents)

Wang J, Clark JB, Rhee GS, Fair JH, Reid LM*, Gerber DA* [*co-senior authors]. (2003) Proliferation and hepatic differentiation of adult-derived murine progenitor cells. Cells Tissues Organs. 173(4):193-203.

Liu H, Di Cunto F, Imarisio S, Reid LM. (2003) Citron kinase is a cell cycle-dependent, nuclear protein required for G2/M transition of hepatocytes. J Biol Chem.278(4):2541-8.

Kubota H, Storms RW, Reid LM. (2002) Variant forms of alpha-fetoprotein transcripts expressed in human hematopoietic progenitors. Implications for their developmental potential towards endoderm. J Biol Chem. 277(31):27629-35.

Macdonald JM, Xu A, Kubota H, LeCluyse E, Hamilton G, Liu H , Rong Y, Moss N, Lodestro C , Luntz T, and Reid LM. (2002) Lineage biology and Tissue Engineering of Liver. In: Methods for Tissue Engineering. R. Lanza, editor. Academic Press, NY.

Wolfe SP, Hsu E., Reid LM*, and Macdonald JM*[co-senior authors*] (2002). A Novel Multicoaxial Hollow Fiber Bioreactor for Adherent Cell Types. Part I: Hydrodynamic Studies. Biotechnology and Bioengineering. 77:83-90.

R Susick, N Moss, H Kubota, E LeCluyse, G Hamilton, T Luntz, J. Ludlow, J. Fair, D. Gerber, K Bergstrand, J. White, A. Bruce, O. Drury , S. Gupta and LM Reid. (2001) Hepatic Progenitors and Strategies for Liver Cell Therapies. Ann. N.Y. Acad. Sci. 944:334-343.

Xu A, Luntz T, Macdonald J, Kubota H, Hsu E, London R, and Reid LM. (2000) Stem Cells, Lineage Biology and Liver. In: Principles of Tissue Engineering, R. Lanza, R. Langer, and J Vacanti, editors, Lands Press, NY. pp. 559-598.

Kubota H and Reid LM. (2000) Clonogenic hepatoblasts, common precursors for hepatocytic and biliary lineages, are lacking classical major histocompatibility complex class I antigen. Proc. Natl. Acad. Sciences USA. 97 (22): 12132-12137.

Macdonald J, Griffin J, Kubota H, Griffith L, Fair J and Reid LM. (1999) Bioartificial Livers. In: Handbook on Encapsulated Cells and Bioartificial Organs. pp 254-289.

Sigal SH, Rajvanshi, Gorla GR, Sokhi RP, Saxena R, Gebhard DR, Reid LM* and Gupta S*. (1999) Partial hepatectomy-induced polyploidy attenuates hepatocyte replication and activates cell aging events. American Journal of Physiology. 276 (Gastrointest.Liver Physiol.) 39:G1260-G1272.[*co-senior authors]

Sigal SH, Gephardt D, Gupta S, Neufeld D and Reid LM. (1995) Evidence for temrinal differentiation in the liver. Differentiation 59: 35-42.

Brill S, Zvibel I and Reid LM . (1995) Maturation-dependent changes in the regulation of liver-specific gene expression in embryonal versus adult primary liver cultures. Differentiation 59: 95-102.

Sigal SH, Rajvanshi P, Reid LM and Gupta S. (1995) Demonstration of differentiation in hepatocyte progenitor cells using dipeptidyl peptidase IV deficient mutant rats. Cell Mol Bio Res 41:39-47.

Brill S, Sigal SH, Zvibel I, Fiorino A, Holst P, Somasundaran U, and Reid LM. (1994) Extracellular matrix regulation of growth and gene expression in liver cell lineages and hepatomas. In: Liver Biology and Pathobiology. Raven Press, New York. pp. 869-897.

Sigal SH, Brill S, Reid LM*, Zvibel I, Gupta S, Hixson DC, Faris RH, and Holst P* [co-senior authors] (1994). Characterization and enrichment of fetal rat hepatoblasts by immunoadsorption ("panning") and fluorescence activated cell sorting. Hepatology 19:999-1006.

Zern, M.A., and Reid, L.M., editors. (1993). Extracellular Matrix: Its Chemistry, Biology and Pathobiology. Marcel Dekker, Inc., New York, N.Y., David van Theil, Editor-in-Chief.

Sigal S.H., Brill, S., Fiorino, A.S., and Reid, L.M. (1992). The liver as a stem cell and lineage system. Am.J.Physiol. 263: G139-G148.

Reid LM, Sigal SH, Fiorino A, Brill S, Holst P. (1992) A gradient of extracellular matrix in the space of Disse. Hepatology 15:1198-1203 (editorial).

Zvibel I., Halay E., Reid, L.M. (1991). Heparin/hormone regulation of autocrein growth factor mRNA synthesis and abundance Relevance to clonal growth of tumors. Mol. and Cell. Biol. 11:108-116.

Doerr R, Zvibel I, Chiuten D, D'Olimpio J, and Reid LM. (1989) Clonal growth of tumors on tissue-specific biomatrices and correlation with organ site specificity of metastases. Cancer Res. 49:384-392.

Spray DC, Fujita M, Saez JC, Choi H, Watanabe T, Hertzberg E, Rosenberg LC, and Reid LM. (1987) Proteoglycans and glycosaminoglycans induce gap junction synthesis and function in primary liver cultures. J. Cell Biol. 105:541-551.

Muschel R, Khoury G, and Reid LM. (1986) Regulation of insulin mRNA abundance and adenylation: Dependence on hormones and matrix substrata. Mol Cell Biol 6:337-341.

Jefferson DM Clayton D, Darnell JE, Jr and Reid LM. (1984) Posttranscriptional modulation of gene expression by media conditions in cultured rat hepatocytes. Mol Cell Biol 4:1929-1934.

Enat R, Jefferson DM, Ruiz-Opazo N, Gatmaitan Z, Leinwand L and Reid LM. (1984) Hepatocyte Proliferation in vitro: Its dependence on the use of serum-free, hormonally defined medium and substrata of extracellular matrix. Proc. Natl.Acad. Sciences USA 81:1411-1415.

Gatmaitan Z, Jefferson DM, Ruiz-Opazo N, Biempica L, Arias I, Leinwand L, and Reid LM. (1983) Regulation of growth and differentiation of a rat hepatoma cell line by synergistic interactions of hormones and collagenous substrata. J. Cell Biol. 97:1179-1190.

Reid LM, Minato N, Gresser I, Holland J, Kadish A, and Bloom B. (1981) Influence of anti-mouse interferon on the growth and metastasis of virus persistently infected tumor cells and of human prostatic tumors in athymic nude mice. Proc. Natl. Acad. Sci. USA 78: 1171-1175.

Minato N, Bloom B, Jones C, Holland J, and Reid LM. (1979) Mechanism of rejection of virus persistently infected tumor cells by athymic nude mice. J. Exp. Med. 149: 1117-1133.