Germ Layer Lineage Stem Cells

A second category of adult precursor cells consists of the germ layer lineage ectodermal, mesodermal, and endodermal stem cells. These stem cells demonstrate extensive capabilities for self-renewal, far exceeding the mitotic clock of 50-70 population doublings for differentiated cells and lineage-committed tissue-specific cells. Germ layer lineage stem cells are telomerase-positive. This characteristic is consistent with their extensive capabilities for self-renewal. They retain this capacity as long as they remain uncommitted to particular tissue and cell types. However, after germ layer lineage stem cells commit to a particular tissue type, they become tissue-specific progenitor cells. As with all progenitor cells, they then exhibit a mitotic clock of 50-70 population doublings before programmed cellular senescence and death occurs (2,6-10).

Because of its developmental lineage (see Fig. 1), the germ layer lineage ectodermal stem cell (EctoSC) has the potential to form gonadotrophs, somatotrophs, thyrotrophs, corticotrophs, mammanotrophs, amine precursor uptake decarboxylase (APUD) cells, chromaffin cells, enterochromaffin cells, pheochromocytes, adrenal medulla, parafollicular-C-cells, neurons, astrocytes, oligodendrocytes, dorsal root ganglion cells, sympathetic ganglion cells, para-sympathetic ganglion cells, ependyma, keratinocytes, hair, nails, sweat glands, sebaceous glands, apocrine glands, salivary gland mucous cells, salivary gland serous cells, lens, corneal epithelium, enamel, olfactory epithelium, retina, iris, smooth muscle (sphincter & dilator pupillae), ciliary body, pituicytes, hypo-

thalamus, thalamus, pinealocytes, spinal nerves, Schwann cells, motor nerve endings, Meissner's touch corpuscles, Merkel's disks, Krause's end bulbs, free nerve endings, Pacinian touch corpuscles, melanocytes, odontocytes, cemento-cytes, heart valves, cardiac skeleton, pulmonary trunk, chordae tendinae, ascending aorta, cardiac cushions, membranous atrial septum, membranous ventricular septum, and corneal endothelium (3,5,11). Thus far we have induced over 20 of these differentiated cell types. We have developed assay procedures to verify the identity of 10 of these cell types within populations of germ layer lineage ectodermal stem cells derived from humans and rats (see Table 1).

Because of its developmental lineage (see Fig. 1), the germ layer lineage mesodermal stem cell has the potential to form cells of the adrenal cortex, Sertoli cells, interstitial cells of Leydig, ovarian stroma, follicular cells/granulosa cells, thecal cells, skeletal muscle, smooth muscle, cardiac muscle, unilocular adipocytes, multilocular adipocytes, fibrous connective tissues, dermis, tendons, ligaments, dura mater, arachnoid mater, pia mater, organ capsules, organ stroma, tunica adventitia, tunica serosa, fibrous scar tissue, hyaline cartilage, articular cartilage, elastic cartilage, growth plate cartilage, fibrocartilage, endochondral bone, intramembranous bone, arterial endothelial cells, venous endothelial cells, capillary endothelial cells, lymphoidal endothelial cells, sinusoidal endothelial cells, erythrocytes, monocytes, macrophages, T-lymphocytes, B-lymphocytes, plasma cells, eosinophils, basophils, Langerhans cells, dendritic cells, natural killer cells, bone marrow stroma, proximal convoluted tubule, distal convoluted tubule, loop of Henle, podocytes, juxtaglomerular cells, mesangial cells, transitional epithelium, seminiferous tubules, tubuli recti, rete testis, efferent ductules, ductus epididymis, ductus deferens, seminal vesicle, ejaculatory ducts, fallopian tubes, uterine endometrium, uterine glands, and upper two-thirds of the vagina (3,6-8,11). Thus far we have induced more than 40 of these cell types and have developed assay procedures to objectively verify 25 of them within populations of germ layer lineage mesodermal stem cells derived from humans and rats (see Table 1).

Because of its developmental lineage (see Fig. 1), the germ layer lineage endodermal stem cell has the potential to form thyroid follicular cells, parathyroid oxyphil cells, parathyroid chief cells, pancreatic a cells, pancreatic p cells, pancreatic 5 cells, pancreatic poly peptide-P cells, brush cells, goblet cells, Clara cells, type I alveolar cells, type II alveolar cells, epithelium of esophagus, gastric mucous cells, gastric parietal cells, gastric chief cells, cardiac glands, gastric glands, pyloric glands, Brunner's glands, epithelium of small intestine, epithelium of large intestine, epithelium of appendix, epithelium of rectum, epithelium of gall bladder, goblet cells, hepatocytes, biliary cells, canalicular cells, oval cells, acinar cells, lining epithelium of pharyngeal pouches, lining of middle ear, pharyngeal tonsils, and thymus (1-3,11). We have induced more than 20 of these cell types and have developed assay procedures to objectively verify 11 of them within rodent and human germ layer lineage endodermal stem cell lines (see Table 1).

Young et al. (6,8) studied the expression of CD markers in germ layer lineage stem cells generated from human fetal, neonatal, adult, and geriatric donors. They found that the mesodermal stem cell exhibited CD10, CD13, CD34, CD56, CD90, and MHC-I CD markers. They did not find expression of CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD9, CD11b, CD11c, CD14, CD15, CD16, CD18, CD19, CD20, CD22, CD23, CD24, CD25, CD31, CD33, CD36, CD38, CD41, CD42b, CD45, CD49d, CD55, CD57, CD59, CD61, CD62E, CD65, CD66e, CD68, CD69, CD71, CD79, CD83, CD95, CD105, CD117, CD123, CD135, CD166, Glycophorin-A, HLA-DRII, FMC-7, Annexin-V, or LIN cell surface markers. Other investigators have observed some variations on this pattern (3). Once induced to differentiate, germ layer lineage stem cells demonstrate pheno-typic differentiation expression markers specific for their tissues and characteristic of the germ layer from which the cell was derived (see Table 1) (2,3).

Germ layer lineage stem cells are responsive to proliferation agents such as platelet-derived growth factors. They exhibit contact inhibition at confluence in vitro. These stem cells are unresponsive to lineage-induction agents that have actions outside their germ layer tissue lineage. For example, germ layer lineage mesodermal stem cells are unresponsive to brain-derived neurotrophic factor (which acts on ectodermal lineage cells) and hepatocyte growth factor (which acts on endodermal lineage cells), but are responsive to bone morphogenetic protein-2 (which acts on mesodermal lineage cells). They are unresponsive to progression agents that accelerate the time frame of expression for tissue-specific phenotypic differentiation expression markers. Germ layer lineage stem cells remain quiescent in a serum-free environment lacking proliferation agents, lineage-induction agents, progression agents, and inhibitory factors (2-4,9,10). Ectodermal, mesodermal, and endodermal germ layer lineage stem cells compose approximately 9% of the precursor cell population. These stem cells are located in all tissues of the body throughout the life-span of an individual. The preferred harvest sites for germ layer lineage stem cells are skeletal muscle, dermis, bone marrow, or an organ of the respective germ layer lineage (2,3).

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