Follow up on "Obama's Ethics Tough On Approval of New Stem Cell Lines"

The NIH has rejected 47 stem cell lines carrying a variety of disease causing mutations reports the Chicago Sun-Times.  The lines developed from preimplantation genetic diagnosis at the Reproductive Genetics Institute failed to receive the "OK" for federal funding because of a problem in the patient consent form.  I reported on the initial controversey in a post a few weeks ago.

The lines are potentially a gold mine for researchers studying the relationship between the mutated gene and the development of diseases such as muscular dystrophy and huntington's disease.  The stem cell lines will not be available for federally funded research and studies utilizing these lines must now be funded soley through private resources.

A Link Between Liver Development, Regeneration, and Carcinogensis

The liver has long been recognized as having marked capacity for regeneration. However, it is only lately that we have been able to characterize and define the stem cell populations that contribute to the regeneration of the liver. Several new biomarkers have enabled a new understanding of human hepatic stem cells which has changed the way we think about the relationship between liver development, regeneration, and carcinogenesis. The following is a summary of recent advances in the field of stem cell biology relevant to liver pathology.

Research from the group of Lola M. Reid at the University of North Carolina is bringing the human hepatic stem cells (hHpSC) into clear focus. A study from 2008 published in Hepatology found hHpSC concentrated in the ductal plate during development and restricted to the terminal biliary ducts (canals of hering) in normal adult tissues.  hHpSC are a separate population from the Hepatoblast (HB) which had formerly been regarded as the only stem cell population in the liver. The article defines these two distinct cell populations...

The combination of antigens that uniquely defines hHpSCs (EpCAM, NCAM, CK19, and albumin, but not AFP) is evident in the ductal plates in fetal and neonatal livers and in the canals of Hering in adults. The combination of antigens uniquely defining hHBs (EpCAM, ICAM, CK19, albumin, AFP) is not in cells in the ductal plates but is present in cells throughout the parenchyma of fetal and neonatal livers and in individual cells or small groups of cells connecting to one end of, or adjacent to, a canal of Hering in pediatric and adult livers.

This new perspective allowed the further study of the role these primitive compartments play in the regeneration of human livers. The authors found that the biliary ductular reaction, the putative progenitors that arise from the canals of hering following liver injury, is an expansion of progenitors originating from the hHpSC and HB. Interestingly though, the population that gives rise to the ductular reaction differs depending on the type of injury.

The primary regenerative responses to liver necrosis involve expansion of the hHpSCs (Ep-CAM+, NCAM+, but AFP negative), whereas those in biliary cirrhosis involves presumptive hHBs (EpCAM+at the plasma membrane and ICAM+, AFP+). In hepatic cirrhosis, both populations can be involved.

In a studied carried out by another group, Zhou et al., (Hepatology 2007) showed that a similar set of markers was useful in distinguishing the lineages that the ductular reactions cells contribute to. This study generated beautiful images that depict the ductular reactions becoming bipolarized into hepatocytic and cholangiocytic lineages. An investigation into the transcription factors that are expressed in these ductular reactions confirmed that developmental genes are reactivated and similarly showed differences in expression profiles between injury groups.

I have previously posted on the role of stem cells in tumorigenesis, and hepatic stem cells are a prime suspect for the originating cell of hepatocellular carcinoma (HCC). Last year, Yamashita et al, found an aggressive subset of HCC that contains EpCAM+ cells with the molecular signature of hHpSC. The authors of this study further demonstrated that the EpCAM+ cells are a tumor initiating population and that molecular knockdown of the EpCAM-WNT signalling pathway can attenuate tumor growth. This provides a therapuetics strategy whereby a patient's HCC is assayed for EpCAM expression to determine if anti-EpCAM therapies are indicated. Adecatumumab, an Anti-EpCAM monclonal antibody, has already been used in clinical trials for breast and other cancers. This is an example of a personalized medicine/ targeted molecular therapeutics strategy that is similar to the algorithms now in use for Her2 positive breast cancers and EGFR+/K-Ras wild-type colon cancers.

A pattern is emerging that shows that some tissue stem cells re-express the molecular regulators that govern the embryonic development during regeneration. Further, our new understanding of this link between development and regeneration has opened up new therapeutic areas for cancers that exploit the molecular pathways and mechanisms of the stem cell state for tumor growth, invasions, and metastasis. This is just one area where our pursuit of stem cell research, both embryonic and adult, will lead to new therapeutics for diseases with few, if any, treatments that work.



Zhang L, Theise N, Chua M, & Reid LM (2008). The stem cell niche of human livers: symmetry between development and regeneration. Hepatology (Baltimore, Md.), 48 (5), 1598-607 PMID: 18972441

Zhou H, Rogler LE, Teperman L, Morgan G, & Rogler CE (2007). Identification of hepatocytic and bile ductular cell lineages and candidate stem cells in bipolar ductular reactions in cirrhotic human liver. Hepatology (Baltimore, Md.), 45 (3), 716-24 PMID: 17326146

Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin LX, Wauthier E, Reid LM, Minato H, Honda M, Kaneko S, Tang ZY, & Wang XW (2009). EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology, 136 (3), 1012-24 PMID: 19150350

Limaye PB, Alarcón G, Walls AL, Nalesnik MA, Michalopoulos GK, Demetris AJ, & Ochoa ER (2008). Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development. Laboratory investigation; a journal of technical methods and pathology, 88 (8), 865-72 PMID: 18574450

Primer on stem cell biology

Questions such as "So what makes this a stem cell?" and "what's the difference between progenitors and stem cells anyway?" have been asked to me before by both attending physicians and residents or fellows.   Stem cell biology and regenerative medicine is truly a multidisciplinary field and one of the greatest advances in science and technology.  This post is a primer on stem cell biology focuses mostly on adult tissue stem cells and is intended for physicians interested in becoming involved in regenerative medicine.  The following terms are a necessary starting point for discussing the facets that underlie this field and over time I intend to expand upon the concepts presented here.

Stem cells are inherently different from terminally differentiated cells. They posses the capacity for self renewal - the ability maintain an undifferentiated state through cellular divisions.  Many molecular factors have been elucidated that regulate this process such as growth factors (WNT and FGF) and transcription factors (LGR5 and Ascl2 in the intestinal crypt stem cell).  Self renewal is typically proven by animal model lineage studies or through in vitro culture and colony forming assays for isolated human tissues.  Stem cells in adult tissues are mostly quiescent which, experimentally speaking, gives rise to the term label retaining cell.  Controlling the factors that regulate self renewal is currently a major problem slowing the development of regenerative cellular therapeutics and an area of intensive research.

Watch Irv Weissman, director of Stanford's Stem Cell Biology and Regenerative Medicine Institute, speak about the differences between adult and embryonic stem cells.

A progenitor is a cell that is not fully differentiated and thus has an immature phenotype or function. Progenitors may exist in many forms before becoming fully mature and differentiated.  Progenitors are usually the result of an asymmetric stem cell division; hence, they are progeny that are not maintained in an undifferentiated state. This occurs as a coordinated process between extrinsic factors, such as basement membrane components or growth factors and intrinsic regulators such as transcription factors. A population of these progenitors is often referred to as a transit amplifying compartment due to their marked capacity for proliferation.

Take for example the stem cells that reside in the crypts of the intestinal epithelium (shown below). The surface epithelial cells have a finite lifespan and will be sloughed off into the lumen when they are too old and senescent to function. The stem cells in the crypts, however, exist for the lifetime of the organism due to their capacity for self renewal.

from http://www.pnas.org/content/104/39/15418/F5.expansion.html

I have emphasized the word "usually" in the above definition since progenitor populations may not be so well defined, especially during disease processes and tissue regeneration.  The result of one of these processes may be the emergence or induction of a facultative progenitor from cells other than classically defined stem cells or transit amplifying cells.  Furthermore, a population of stem cells may be reserved for mediating the process of regeneration that follows only after severe injury. These reserve stem cells may reside in a completely separate microanatomical compartment which may serve to protect them from injury. When considering this population, we can make a distinction between these reserve stem cells and homeostatic stem cells such as those in the intestinal crypts.  This will be critical when examining the role of progenitors and stem cells in disease processes such as metaplasia and neoplasia.  Future posts will focus on this topic as it relates to both adult and embryonic stem cell studies.

See the Wikipedia article on stem cells that includes many other terms relevant to lineages and potency.