Fig. 1.20 Embryonalstemcells.Thezygote,formedbytheunionofspermandegg,dividestoformblastocysts,andtheinnercellmassoftheblastocystgeneratestheembryo.Thepluripotentcellsoftheinnercellmass,knownasembryonicstem(ES)cells,canbeinducedtodifferentiateintocellsofmultiplelineages.Intheembryo,pluripotentstemcellscanasymmetricallydividetoyieldaresidualstablepoolofEScellsinadditiontogeneratingpopulationsthathaveprogressivelymorerestricteddevelopmentalcapacity,eventuallygeneratingstemcellsthatarecommittedtojustspecificlineages.EScellscanbeculturedinvitroandinducedtogiverisetocellsofallthreegermlayers.
Fig. 1.21 Stem cell niches in various tissues. (A) Skin stem cells are located in the bulge area of the hair follicle, in sebaceous glands, and in the lower layer of the epidermis. (B) Small intestine stem cells are located near the base of the crypt, above Paneth cells. (C) Liver stem cells (oval cells) are located in the canals of Hering (thick arrow), structures that connect bile ductules (thin arrow) to parenchymal hepatocytes. Bile duct cells and canals of Hering are stained here with an immunohistochemical stain for cytokeratin 7. (C, Courtesy Tania Roskams, MD, University of Leuven, Belgium.)
Besides hematopoietic stem cells, the bone marrow (and notably, other tissues such as fat) also contains a population of mesenchymal stem cells. These are multipotent cells that can differentiate into a variety of stromal cells including chondrocytes (cartilage), osteocytes (bone), adipocytes (fat), and myocytes (muscle). Because these cells can be expanded to large numbers, they represent a potential means of manufacturing the stromal scaffolding needed for tissue regeneration.
The ability to identify, isolate, expand, and transplant stem cells has given birth to the new field of regenerative medicine. Theoretically, the differentiated progeny of ES or adult stem cells can be used to repopulate damaged tissues or to construct entire organs for replacement. In particular, there is considerable excitement about the therapeutic opportunities for restoring damaged tissues that have low intrinsic regenerative capacity, such as myocardium after a myocardial infarct or neurons after a stroke. Unfortunately, despite an improving ability to purify and expand stem cell populations, much of the initial enthusiasm has been tempered by difficulties encountered in introducing and functionally integrating the replacement cells into sites of damage.
More recently it has been possible to generate pluripotential cells, resembling ES cells, that are derived from the patient into whom they will be implanted. To accomplish this, a handful of genes have been identified whose products can—remarkably—reprogram somatic cells to achieve the “stem-ness” of ES cells. When such genes are introduced into fully differentiated cells (e.g., fibroblasts), induced pluripotent stem cells (iPS cells) are generated (
Fig.
1.22 ), albeit at low frequency. Because these cells are derived from the patient, their differentiated progeny (e.g., insulin-secreting β-cells in a patient with diabetes) can be engrafted without eliciting an immunologically mediated rejection reaction that would occur if the differentiated cells were derived from ES cells obtained from another donor.