The identification of tissue-specific stem cells has radically reshaped the conceptual framework that guides the development of therapeutic strategies targeting cancers, degenerative diseases, and post-traumatic injuries. Initially characterized in the hematopoietic system, cells able to elaborate some or all cell types in a given cellular compartment have now been identified in many other tissue types (3
). Experimental approaches to study these cells have centered on the Hh and Wnt pathways, which bring with them an impressive set of genetic and biochemical observations that can be leveraged into mechanistic models amenable to interrogation. In this respect, our understanding of the Hh and Wnt pathways continues to influence almost all aspects of stem cell research.
The role of Wnt proteins in tissue homeostasis is best characterized in the intestinal epithelium, where signaling promotes expansion and differentiation of stem cells located within the crypt base. Genetically mediated disruption of pathway response at the level of ligand/receptor interactions (46
) or transcription (47
) effectively inhibits formation of downstream epithelial lineages, resulting in a loss of the epithelial lining and altered tissue architecture. On the other hand, 80–90% of all colorectal cancer incidents harbor mutations in the APC
gene that give rise to a truncated APC protein and aberrant pathway activation (48
). Biallelic loss of APC induces aberrant induction of β-catenin-mediated transcription of growth-promoting programs, including upregulation of the proto-oncogene c-Myc
). The convergence of phenotypic changes in the gastrointestinal (GI) epithelium that stem from perturbations of the Wnt/β-catenin pathway support a pivotal function of this pathway in controlling the behavior of a multipotent cell population relevant in both normal and disease contexts. The Wnt/β-catenin target gene Lgr5
(leucine-rich repeat-containing G protein–coupled receptor 5) was found to function as a marker that can be used to isolate cells with the capacity to elaborate all of the distinct epithelial cell types in the GI and skin. This discovery solidifies the role that essential Wnt molecules play in stem cell self-renewal in some tissues (51
The waning capacity of tissues to elaborate normal cell types following injury is an inevitable condition associated with aging (52
). In lieu of normal tissue regeneration, fibrosis constitutes a common response to injury in aged animals. The selection of a transcriptional program that favors fibrogenesis rather than normal cell lineage recapitulation in muscle repair, for example, is observed with age-related increases in humoral Wnt protein activity (53
). In the same vein, changes in the function of the type II diabetes gene Tcf7l2/Tcf4
, encoding a DNA-binding protein that regulates transcriptional responses to Wnt proteins, likely accelerate age-dependent erosion of pancreatic β-cell function (54
). These observations, in addition to many others reviewed in References 10
, support a broad role for homeostatic levels of Wnt pathway responses in preventing degenerative diseases.
The inception and maintenance of some tissues are similarly dependent on Hh pathway activity. The phenotypic outcomes from targeted deletion of the Sonic Hedgehog (Shh
) gene include derangements in body patterning and a range of neurological defects such as cyclopia and neural tube malformation (56
). A role for Hh in neuronal tissue appears to be retained in adults, where Hh secreted by Purkinje cells promotes granule-cell precursor differentiation into neurons; at the same time, Hh inhibits stem cell apoptosis within the external granular layer (57
). Loss of function of the Hh pathway suppressor Ptch frequently gives rise to medulloblastoma development both in sporadic incidents and in hereditary Gorlin’s tumor syndrome (60
). Patients afflicted with the latter disease are often additionally diagnosed with basal cell carcinoma and rhabdomyosarcoma, reflecting the roles of Hh in skin and muscle homeostasis.
Additional observations relating to functions of Hh and Wnt proteins in tissue maintenance that directly bear on therapeutic efforts to target them are noted here. First, these two pathways function collaboratively and with other signaling pathways to achieve developmental, regenerative, and disease-associated outcomes (61
). Thus Hh and Wnt pathway-modulating agents that are typically defined by simplistic in vitro readouts of pathway activity will most certainly exhibit unanticipated effects within in vivo settings. Particularly in cancerous contexts, the main lines of communication between tumor and stroma are mediated by the concerted actions of the Hh and Wnt ligands, which are often difficult to model in vitro (71
). Second, consideration must be given to so-called noncanonical responses to Wnt and Hh ligands that do not involve the well-documented gene transcription changes historically associated with ligand engagement (10
). These include Wnt- and Hh-mediated responses that influence cytoskeletal behavior, cell polarity, and cell migration. Likely, the roles of these activities in tissue homeostasis and disease are underestimated, given the dearth of readily accessible readouts for monitoring their status. Thus, despite the wealth of knowledge that relates to the biology of the Hh and Wnt molecules, unanticipated challenges certainly will arise.