Faculty Bibliography

Cell doctrine is the foundational paradigm of Euro-American medicine and biology. Even without stepping outside that tradition, one may imagine alternate models of the body such as a fluid model in which cells do not exist or a model wherein cells are described as overlapping fields of molecular organization in space and time. With a complexity analysis of cell biology, we find that the existence of cells as unitary entities, as things, is contingent on the level of scale at which the body is observed. Therefore, alternate models of the body may be conceived that are specific and appropriate to other levels of scale. These ideas suggest that some bodily phenomena, particularly from Asian traditions, which have previously resisted explanation from within the cell-based Euro-American tradition (e.g., acupuncture) may be productively investigated with one or more of these other models. Additionally, the seemingly metaphorical concepts from Tibetan medicine of the coarse, energy, and subtle bodies may represent precise, though somewhat poetically expressed representations of the body at different levels of scale.

While skepticism regarding the possibilities for a productive meeting (metaphorically or actual) between Western medicine and biology and older healing and health practices of traditional cultures may be prevalent, there are many theoretical points of meeting and much experimental data to suggest that cognitive-behavioral practices (C-Bp) of the latter may induce testable and reproducible phenomena for the former. Such modulation or modification of tissue regeneration by C-Bp presumably must work through systemic signaling of some kind. Several possible mechanisms for such signaling are recognized and will be reviewed here: humoral, neurological, cell trafficking, and bioelectromagnetic/energy mediated. Nonetheless, while cultures and techniques may be varied, human bodies are more alike than dissimilar. We indicate that great profit may be had for all participating cultures in establishing a common language, shared criteria for designing experiments and interpreting data, and cooperative goals for the promotion of tissue integrity and regeneration.

The orientation of this volume and the Longevity and Optimal Health: Integrating Eastern and Western Perspectives conference is that there is abundant evidence in the scientific and medical literatures that the diligent practice of certain yoga-meditational regimens can lead to a spectrum of health enhancements, ranging from modest to profound, and that these can be investigated in a scientifically rigorous fashion. This overview will summarize these possibilities regarding improved human longevity, regeneration, and protection of health and serve to introduce the perspectives of conference participants from all of the traditions represented.

Intestinal crypt stem cells establish clonal descendants. To determine whether the pancreas is patterned by a similar process, we used embryonic stem (ES) cell chimeric mice, in which male ES cells were injected into female blastocysts. Fluorescence in situ hybridization for the Y chromosome (Y-FISH) revealed clonal patterning of ES-derived cells in the adult mouse small intestine and pancreas. Intestinal crypts were entirely male or entirely female. Villi contained columns of male or female epithelial cells, consistent with upward migration of cells from the crypts which surround them. Within the exocrine pancreas, acini were entirely male or entirely female, consistent with patterning from a single stem/progenitor cell. Pancreatic islets contained a mixture of male and female cells, consistent with patterning from multiple progenitors. Male-female chimeric mice demonstrate that the adult mouse exocrine pancreatic acinus is patterned from a single stem/progenitor cell, while the endocrine pancreas arises from multiple progenitors.

Human livers contain two pluripotent progenitors: hepatic stem cells and hepatoblasts. The hepatic stem cells uniquely express the combination of epithelial cell adhesion molecule (EpCAM), neural cell adhesion molecule (NCAM), cytokeratin (CK) 19, albumin +/-, and are negative for alpha-fetoprotein (AFP). They are precursors to hepatoblasts, which differ from hepatic stem cells in size, morphology, and in expressing the combination of EpCAM, intercellular cell adhesion molecule (ICAM-1), CK19, albumin++, and AFP++. The hepatic stem cells are located in vivo in stem cell niches: the ductal plates in fetal and neonatal livers and canals of Hering in pediatric and adult livers. The hepatoblasts are contiguous to the niches, decline in numbers with age, wax and wane in numbers with injury responses, and are proposed to be the liver's transit-amplifying cells. In adult livers, intermediates between hepatic stem cells and hepatoblasts and between hepatoblasts and adult parenchyma are observed. Amplification of one or both pluripotent cell subpopulations can occur in diseases; for example, hepatic stem cell amplification occurs in mild forms of liver failure, and hepatoblast amplification occurs in forms of cirrhosis. Liver is, therefore, similar to other tissues in that regenerative processes in postnatal tissues parallel those occurring in development and involve populations of stem cells and progenitor cells that can be identified by anatomic, antigenic, and biochemical profiles.

Label retention assays remain the state-of-the-art approach to identify the location of intraorgan epithelial stem cell niches, in situ and in vivo. They are commonly used in organs with rapid cell turnover but have not been applied to the liver, where cell turnover is very slow. We used a sublethal dose of acetaminophen administered coincident with bromodeoxyuridine to load possible hepatic stem cells in mice with label and then administered a second, sublethal chase of acetaminophen to accomplish "washout" of label from transit amplifying cell populations. CONCLUSION: Four possible hepatic stem cell niches are identified by this approach: the canal of Hering (proximal biliary tree), intralobular bile ducts, periductal "null" mononuclear cells, and peribiliary hepatocytes. These results confirm several different and often contradictory lines of investigation regarding the intrahepatic location of stem/progenitor cells and suggest that the liver has a multi-tiered, flexible system of regeneration rather than a single stem/progenitor cell location.