Wednesday, June 2, 2010

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.

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.

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