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PubMed2001

Development of human fetal pancreas after transplantation into SCID mice.

Only a small component of human fetal pancreas consists of beta cells, and yet this tissue is capable of normalizing the blood glucose levels of diabetic recipients when transplanted. The time taken to achieve this goal is several months, during which time the tissue proliferates and eventually differentiates into beta cells. The dynamics of beta cell development have not been described previously. We transplanted human fetal pancreas beneath the renal capsule of immunodeficient mice and analysed the grafts for a period of 12 weeks using antibodies against exocrine cells (lipase), endocrine cells and protodifferentiated duct cells. Exocrine cells constituted 48% of all epithelial cells in the untransplanted pancreas, with duct cells comprising 29% and endocrine cells 16% (beta cells 7%). The percentage of exocrine cells declined with time after transplantation, with only a small number undergoing apoptosis, and the duct cells increased, the values for these two cell types at 12 weeks being 20 and 57%, respectively. Both cell types appeared to proliferate equally for up to 8 weeks after transplantation, but only duct cells thereafter. Endocrine cells began to increase from 8 weeks after transplantation, representing 28% of epithelial cells (beta cells 11%) at this time. Intermediate cells, that is, cells expressing the characteristics of more than one type of mature pancreatic cell, were observed both in the ungrafted pancreas and after transplantation. The commonest intermediate cell type was duct/exocrine, with exocrine/endocrine and duct/endocrine cells also observed, suggesting active transdifferentiation from one cell type to another. We hypothesize that following the transplantation of human fetal pancreatic tissue, exocrine cells mostly transdifferentiate into duct cells and these eventually develop into endocrine cells, in particular beta cells.

Animals↗
PubMed2005

Peripheral blood mononuclear cells acquire myofibroblast characteristics in granulation tissue.

BACKGROUND: Bone marrow-derived cell populations possess progenitor cell capacities. Emerging evidence also suggests significant plasticity of differentiated mononuclear cell lineages. We therefore assessed the distribution of transplanted peripheral blood mononuclear cells (PBMCs) in granulation tissue formation, and evaluated their possible transdifferentiation into myofibroblasts. METHODS: Silastic tubes were inserted into the peritoneal cavity of rats, followed by injection of PKH26-labelled PBMCs isolated from donor animals. At 3, 14 and 21 days, the distribution of PKH26(+) cells as well as their colocalization with myofibroblast/smooth muscle cell [alpha-smooth muscle (alpha-SM) actin] or macrophage markers (ED1/ED2) were determined. RESULTS: Round-shaped PKH26(+) cells accumulated around the implants at 3 days, while myofibroblasts were rare. Later, peritoneal granulation tissue constituted an inner, multilayered capsule primarily comprising alpha-SM actin(+) cells that was surrounded by more loosely organized inflammatory connective tissue. PKH26-labelled, spindle-shaped cells were abundantly found in tissue capsules. As a key finding, granulation tissue at 14 and 21 days contained cells with both PKH26 and alpha-SM actin labelling. Accordingly, a subpopulation of cells staining positive for macrophage markers showed a spindle-shaped morphology and alpha-SM actin expression. CONCLUSIONS: Transplanted PBMCs contribute to granulation tissue, and acquire myofibroblast characteristics during de novo tissue formation. Mononuclear cells may transdifferentiate into myofibroblast-like cells within an inflammatory environment.

Actins↗
PubMed2006

Carcinogenesis driven by bone marrow-derived stem cells.

The overall mechanism of bone marrow-derived stem cell (BMDC) trans-differentiation seems to be simple: BMDCs trans-differentiate as referred to the blueprint, which is given by the tissue itself. Thereby, the blueprint can be the local tissue micro-environment (defined by the tissue-specific cytokine, chemokine, adhesion molecule pattern, etc.), it can be a single cell (cell fusion), or it can be a combination of both. In fact stem cell trans-differentiation is a complex not yet fully understood process. In between the start- and stop-points of transdifferentiation several gene reprogramming steps have to occur in a sequential step-by-step manner, for which a defined set of instructions is a prerequisite to ensure an accurate transdifferentiation. However, a recent study indicated that the ability of BMDCs - to adopt tissue function by reading its blueprint - seems to be a double-edged sword since BMDCs that have received a faulty blueprint, provided by chronically inflamed tissue, trans-differentiated into a neoplastic phenoytpe. Here, we review the importance of an accurate blueprint for BMDC trans-differentiation and discuss a model showing that BMDCs might contribute to overall tumor development due to recruitment to tumor tissue.

Animals↗
PubMed1996

E-cadherin transforms embryonic corneal fibroblasts to stratified epithelium with desmosomes.

Important and precisely regulated transitions in tissue phenotype from epithelium to mesenchyme and from mesenchyme to epithelium occur in the developing embryo. The gene for E-cadherin has been shown to cause fibroblastic cell lines to become epithelioid in culture. We asked whether or not the activities of the E-cadherin gene could cause a definitive embryonic mesenchyme to transdifferentiate into an epithelial phenotype. Primary corneal fibroblasts from 6- to 7-day-old chick embryos were contransfected by impact loading with plasmids containing E-cadherin and Neo genes and selected in G418. The fibroblasts expressing E-cadherin aggregate, localize E-cadherin to lateral surfaces, and form stratified epithelia that develop zonulae occludentes and adherentes, connexin 43, cytokeratin, desmoplakin, and desmosomes. Vimentin intermediate filaments persist and no basement membranes appear, even though the cells synthesize laminin and type IV collagen. Our study is the first to demonstrate the ability of E-cadherin to induce fibroblasts to form desmosomes and stratified epithelia. The primary embryonic fibroblasts apparently have more developmental potential to transdifferentiate into epithelia than do the fibroblastic cell lines previously studied. We conclude that E-cadherin is likely to play an important role in transformation of mesenchyme to epithelium in the embryo.

Animals↗
PubMed1995

Type IV collagen in the basement membrane of the corneal epithelium after alkali burns in guinea pigs.

To investigate the changes in the corneal epithelial basement membrane following an alkali burn, we examined the immunolocalization of type IV collagen and laminin in the eye of the guinea pig burned with alkali. The burn damaged the corneal, limbal and conjunctival epithelium. After regeneration, basement membrane was interrupted, as indicated by laminin immunoreactivity. Type IV collagen immunoreactivity was transiently expressed in the early healing phase in the epithelial derived from both the cornea and conjunctiva, but was not seen in the normal corneal epithelial basement membrane. Later in the healing process, following transdifferentiation of the conjunctival epithelium into a cornea-like epithelium, its type IV collagen immunoreactivity was weaker than that in the basement membrane of the nontransdifferentiated epithelium. Conjunctival transdifferentiation during healing may have led to transient development of type IV collagen immunoreactivity.

Animals↗
PubMed2003

Insulin-like growth factor-I and its receptor in neovascular age-related macular degeneration.

PURPOSE: The insulin-like growth factor (IGF)-I protein is a growth-promoting polypeptide that can act as an angiogenic agent in the eye. The purpose of the current study was to localize the expression of IGF-I and its receptor (IGF-IR) mRNA and IGF-IR protein in situ in the normal human eye and to examine the presence of expression in eyes with neovascular age-related macular degeneration (AMD). METHODS: Formalin-fixed, paraffin-embedded slides of 4 normal control eyes and 14 eyes with choroidal neovascularization (CNV) secondary to AMD were examined. Three eyes with proliferative diabetic retinopathy were studied as the positive control. IGF-I and IGF-IR mRNA was detected by in situ hybridization with digoxigenin-labeled RNA probes. IGF-IR protein was studied by immunohistochemistry. RESULTS: In the normal retina, IGF-I and IGF-IR mRNA expression was found throughout the neuroretinal layers, in the retinal pigment epithelium (RPE), and in some choriocapillary and retinal capillary endothelial cells. In eyes with CNV we found IGF and IGF-IR mRNA in capillary endothelial cells, some transdifferentiated RPE, and fibroblast-like cells. IGF-IR protein was found in normal eyes in all neuroretinal layers, in the RPE, and in the choroidal vessels. In eyes with CNV, IGF-IR protein was present in the RPE monolayer, in transdifferentiated RPE, and in newly formed vessels. CONCLUSIONS: The colocalization of protein and receptor indicates an autocrine function of IGF-I in the normal human retina. Because IGF-I participates in ocular neovascularization, synthesis of IGF-IR and IGF-I in endothelial cells, RPE cells, and fibroblast-like cells in CNV may point toward a role for this growth factor in the pathogenesis of neovascular AMD.

Adult↗
PubMed2004

Enhanced retinal ganglion cell differentiation by ath5 and NSCL1 coexpression.

PURPOSE: The molecular mechanism underlying retinal ganglion cell (RGC) differentiation is not fully understood. In this study, the role of the basic helix-loop-helix (bHLH) genes ath5 and NSCL1 in RGC differentiation was examined, by testing whether their coexpression would promote RGC differentiation to a greater extent than either gene alone. METHODS: The replication-competent avian RCAS retrovirus was used to coexpress ath5 and NSCL1 through an internal ribosomal entry site. The effect of the coexpression on RGC differentiation was assayed in vivo in the developing chick retina and in vitro in RPE cell cultures derived from day 6 chick embryos. RESULTS: Coexpression of ath5 and NSCL1 in RPE cells cultured in the presence of bFGF promoted RPE transdifferentiation toward RGCs, and the degree of transdifferentiation was much higher than with either gene alone. Cells expressing RGC markers, including RA4, calretinin, and two neurofilament-associated proteins, displayed processes that were remarkably long and thin and often had numerous branches, characteristics of long-projecting RGCs. In the developing chick retina, retroviral expression of NSCL1 resulted in a moderate increase in the number of RGCs, results similar to retroviral expression of ath5. Coexpression of ath5 and NSCL1 yielded increases in RGCs greater than the sum of their increases when expressed separately. CONCLUSIONS: Both in vitro and in vivo data indicate that the combination of ath5 and NSCL1 promotes RGC differentiation to a greater degree than either gene alone, suggesting a synergism between ath5 and NSCL1 in advancing RGC development.

Animals↗
PubMed2005

The crucial role of macrophages in lymphangiogenesis.

Lymphangiogenesis is associated with pathological processes such as the metastatic spread of carcinoma cells and organization of immunologically active lymphocytic infiltrates following organ transplantation. It has not yet been established whether expansion of the lymphatic vascular meshwork is driven by incorporation of progenitor cells or by local endothelial cell division. In this issue of the JCI, Maruyama et al. provide evidence that after mouse corneal transplant, CD11b+ macrophages infiltrate the corneal stroma and transdifferentiate into lymphatic endothelial cell clusters that join existing lymphatic vessels. In complementary in vitro experiments, murine peritoneal macrophages expressed lymphatic endothelial markers and formed vessel-like protrusions. These findings add yet another facet to the plasticity of macrophages, which are already known to transform from naive monocytes into VEGF-C-producing cells. Thus, macrophages support lymphangiogenesis in 2 different ways, either by transdifferentiating and directly incorporating into the endothelial layer or by stimulating division of preexistent local lymphatic endothelial cells.

Animals↗
PubMedDate not supplied

In vivo cell transformation: neogenesis of beta cells from pancreatic ductal cells.

During embryogenesis, islet cells differentiate from primitive duct-like cells. This process leads to the formation of islets in the mesenchyme adjacent to the ducts. In the postnatal period, any further expansion of the pancreatic endocrine cell mass will manifest itself either by a limited proliferation of the existing islet cells, or by a reiteration of ontogenetic development. It is the latter, cell transformation by a process of differentiation from a multipotential cell, that will be referred to in this review as islet neogenesis. To better appreciate the mechanisms underlying islet cell neogenesis, some of the basic concepts of developmental biology will be reviewed. Considerable discussion is devoted to the subject of transdifferentiation, a change in a cell or in its progeny from one differentiated phenotype to another, where the change includes both morphological and functional phenotypic markers. While in vitro studies with fetal and neonatal pancreata strongly suggest that new islet tissue is derived from ductal epithelium, what is not established is whether the primary cell is a committed endocrine cell or duct-like cell capable of transdifferentiation. Next, research in the field of beta-cell neogenesis is surveyed, in preparation for the examination of whether there is a physiological means of inducing islet cell regeneration, and whether the new islet mass will function in a regulated manner to reverse or stabilize a diabetic state? Our belief is that the pancreas retains the ability to regenerate a functioning islet cell mass in the postnatal period, and that the process of cell transformation leading to islet neogenesis is mediated by growth factors that are intrinsic to the gland. Furthermore, it is our contention that these factors act directly or indirectly on a multipotential cell, probably associated with the ductular epithelium, to induce endocrine cell differentiation. In other words, new islet formation in the postnatal period reiterates the normal ontogeny of islet cell development. These ideas will be fully developed in a discussion of the Partial Duct Obstruction (PDO) Model.

Animals↗
PubMed2002

The fate of the terminally differentiated chondrocyte: evidence for microenvironmental regulation of chondrocyte apoptosis.

Chondrocytes contained within the epiphyseal growth plate promote rapid bone growth. To achieve growth, cells activate a maturation program that results in an increase in chondrocyte number and volume and elaboration of a mineralized matrix; subsequently, the matrix is resorbed and the terminally differentiated cells are deleted from the bone. The major objective of this review is to examine the fate of the epiphyseal chondrocytes in the growing bone. Current studies strongly suggest that the terminally differentiated epiphyseal cells are deleted from the cartilage by apoptosis. Indeed, morphological, biochemical, and end-labeling techniques confirm that death is through the apoptotic pathway. Since the induction of apoptosis is spatially and temporally linked to the removal of the cartilage matrix, current studies have examined the apoptogenic activity of Ca(2+)-, Pi-, and RGD-containing peptides of extracellular matrix proteins. It is observed that all of these molecules are powerful apoptogens. With respect to the molecular mechanism of apoptosis, studies of cell death with Pi as an apoptogen indicate that the anion is transported into the cytosol via a Na(+/)Pi transporter. Subsequently, there is activation of caspases, generation of NO, and a decrease in the thiol reserve. Finally, we examine the notion that chondrocytes transdifferentiate into osteoblasts, and briefly review evidence for, and the rationale of, the transdifferentiation process. It is concluded that specific microenvironments exist in cartilage that can serve to direct chondrocyte apoptosis.

Amino Acid Sequence↗
PubMed2000

Comparative evaluation of gene delivery devices in primary cultures of rat hepatic stellate cells and rat myofibroblasts.

BACKGROUND: The hepatic stellate cell is the primary cell type responsible for the excessive formation and deposition of connective tissue elements during the development of hepatic fibrosis in chronically injured liver. Culturing quiescent hepatic stellate cells on plastic causes spontaneous activation leading to a myofibroblastic phenotype similar to that seen in vivo. This provides a simple model system for studying activation and transdifferentiation of these cells. The introduction of exogenous DNA into these cells is discussed controversially mainly due to the lack of systematic analysis. Therefore, we examined comparatively five nonviral, lipid-mediated gene transfer methods and adenoviral based infection, as potential tools for efficient delivery of DNA to rat hepatic stellate cells and their transdifferentiated counterpart, i.e. myofibroblasts. Transfection conditions were determined using enhanced green fluorescent protein as a reporter expressed under the transcriptional control of the human cytomegalovirus immediate early gene 1 promoter/enhancer. RESULTS: With the use of chemically enhanced transfection methods, the highest relative efficiency was obtained with FuGENE6 gene mediated DNA transfer. Quantitative evaluation of representative transfection experiments by flow cytometry revealed that approximately 6% of the rat hepatic stellate cells were transfected. None of the transfection methods tested was able to mediate gene delivery to rat myofibroblasts. To analyze if rat hepatic stellate cells and myofibroblasts are susceptible to adenoviral infection, we have inserted the transgenic expression cassette into a recombinant adenoviral type 5 genome as replacement for the E1 region. Viral particles of this replication-deficient Ad5-based reporter are able to infect 100% of rat hepatic stellate cells and myofibroblasts, respectively. CONCLUSIONS: Our results indicate that FuGENE6-based methods may be optimized sufficiently to offer a feasible approach for gene transfer into rat hepatic stellate cells. The data further demonstrate that adenoviral mediated transfer is a promising approach for gene delivery to these hepatic cells.

3T3 Cells↗
PubMed2003

What is the origin of pancreatic adenocarcinoma?

The concept of pancreatic cancer origin is controversial. Acinar, ductal or islet cells have been hypothesized as the cell of origin. The pros and cons of each of these hypotheses are discussed. Based on the world literature and recent observations, pancreatic cells seem to have potential for phenotypical transdifferentiation, i.e ductal-islet, ductal-acinar, acinar-ductal, acinar-islet, islet-acinar and islet-ductal cells. Although the possibility is discussed that cancer may arise from either islet, ductal or acinar cells, the circumstances favoring the islet cells as the tumor cell origin include their greater transdifferentiation potency into both pancreatic and extrapancreatic cells, the presence of a variety of carcinogen-metabolizing enzymes, some of which are present exclusively in islet cells and the growth factor-rich environment of islets.

Adenocarcinoma↗
PubMed2005

Engraftment of bone marrow-derived epithelial cells.

Discoveries of the ability of bone marrow-derived cells (BMDCs) to differentiate into nonhematopoietic cells have opened up a new field of inquiry in adult stem cell plasticity. There are far more questions than there are answers to date. We and others have investigated whether differentiation occurs in response to tissue damage, what the underlying mechanisms might be, and whether this plasticity may be useful clinically. BMDC have been shown to differentiate into mature-appearing epithelial cells in the lung, liver, gastrointestinal tract, skin, buccal mucosa, and kidney. The mechanism(s) by which cells transition to these nonhematopoietic phenotypes is not yet clear, but possibilities include cell-to-cell fusion, direct differentiation of a nonhematopoietic precursor cell from the BM, and transdifferentiation of a BM cell that had previously been committed to a different phenotype. Data obtained to date support the first two possibilities, and there are no data proving that transdifferentiation is responsible for the engraftment of marrow-derived epithelial cells. Theoretically, the engraftment of marrow-derived cells as nonhematopoietic cell types could be used in either the autologous or the allogeneic setting to restore functional epithelial cells to a diseased organ. For example, a marrow-derived cell that has been transduced to express a specific transgene can continue to express this transgene after it engrafts as a nonhematopoietic epithelial cell in the lung. Analyses of the kinetics of this engraftment suggest that it can be increased within days to weeks following certain types of injury, depending on the tissue examined. Most reports of adult stem cell plasticity show relatively low frequencies of marrow-derived nonhematopoietic cells, on the order of 1 in 10(3) to 1 in 10(4) epithelial cells in many organs being marrow derived. This frequency is likely to be too low to be of therapeutic relevance. Therefore, future efforts will need to be focused on enhancing levels of engraftment.

Animals↗
PubMed2005

Follicular cells acquire sertoli cell characteristics after oocyte loss.

Although it has been suggested that in mammals the loss of female germ cells may induce the masculinization of the ovarian compartment, there has been as yet no conclusive demonstration. To directly address that question, the present study has been designed to determine the fate of follicular cells after oocyte loss. Using gamma-irradiation to selectively deplete oocytes in nongrowing follicles in female rats, we show that follicular cells in oocyte-depleted follicles survive, proliferate, and subsequently acquire morphological characteristics of Sertoli cells: elongated cytoplasm, basal location of the nucleus, and specific Sertoli cell junctions, the ectoplasmic specializations. These Sertoli-like cells express, however, the female-specific marker FOXL2 (Forkhead L2) but not the male sex-specific marker SOX-9 (Sry-type high-mobility-group box transcription factor-9) underlying the maintenance of molecular characteristics of granulosa cells. Before transdifferentiating into Sertoli-like cells, follicular cells of oocyte-depleted follicles initiate the expression of anti-Mullerian hormone and inhibin alpha-subunit that are typically synthesized by granulosa cells from the onset of follicular growth. Experimental modifications of the endocrine balance of the irradiated females show that there is a close relationship between plasma FSH levels and the occurrence of Sertoli-like cells. In addition to providing experimental evidence for the crucial role of the oocyte in granulosa cell phenotype maintenance, these results emphasize that the transdifferentiation of granulosa cells into Sertoli cells occurs in a multistep fashion, requiring the maturation of granulosa cells and depending on the endocrine milieu.

Animals↗
PubMed2003

Squamous cell carcinoma and mammary abscess formation through squamous metaplasia in Smad4/Dpc4 conditional knockout mice.

Smad4 is a central mediator for TGFbeta signals, which play important functions in many biological processes. To study the role of Smad4 in mammary gland development and neoplasia, we disrupted this gene in mammary epithelium using a Cre-loxP approach. Smad4 is expressed in the mammary gland throughout development; however, its inactivation did not cause abnormal development of the gland during the first three pregnancies. Instead, lack of Smad4 gradually induced cell proliferation, alveolar hyperplasia and transdifferentiation of mammary epithelial cells into squamous epithelial cells. Consequently, all mutant mice developed squamous cell carcinoma and/or mammary abscesses between 5 and 16 months of age. We demonstrated that absence of Smad4 resulted in beta-catenin accumulation at onset and throughout the process of transdifferentiation, implicating beta-catenin, a key component of the Wnt signaling pathway, in the development of squamous metaplasia in Smad4-null mammary glands. We further demonstrated that TGFbeta1 treatment degraded beta-catenin and induced epithelial-mesenchymal transformation in cultured mammary epithelial cells. However, such actions were blocked in the absence of Smad4. These findings indicate that TGFbeta/Smad4 signals play a role in cell fate maintenance during mammary gland development and neoplasia.

Abscess↗
PubMed1989

Plasminogen activator expression in F9 teratocarcinoma embryoid bodies and their endoderm derivatives.

Plasminogen activators are believed to play an important role in tissue remodeling and cell migration. During mouse embryogenesis, visceral endoderm secretes urokinase-type plasminogen activator (uPA) whereas parietal endoderm secretes tissue-type plasminogen activator (tPA). Visceral endoderm from F9 embryoid bodies can transdifferentiate into parietal endoderm under the appropriate culture conditions. We have examined at the protein and mRNA levels the type of plasminogen activator expressed in whole embryoid bodies, visceral endoderm and its parietal endoderm derivatives. Our experiments show that the visceral endoderm on F9 embryoid bodies synthesizes and secretes substantial amounts of both tPA and uPA. In contrast, the parietal endoderm derived directly from the visceral endoderm secretes dramatically increased levels of tPA and decreases production of uPA to low or below detectable levels. These data support the finding that visceral endoderm can transdifferentiate to parietal endoderm. In addition, this transition provides an excellent model for studying the molecular basis of the coincident down- and upregulation of the two plasminogen activators as well as their potential function during embryogenesis.

Animals↗
PubMed1991

Expression in non-lens tissues of an enzyme activity related to the 'lens-specific' protein, delta crystallin.

When chick embryo neutral retina (NR) cells are cultured for long periods in vitro, they undergo extensive transdifferentiation into lens and express the lens protein, delta crystallin. We now demonstrate that this process is accompanied by a change in the chromatin conformation of the delta-gene locus from DNAase1-resistant to DNAase1-sensitive in the nuclei of most cells. Transcripts hybridising to a delta probe are also much more prevalent among the in vitro transcription products from lens or transdifferentiated NR culture nuclei, as compared to nuclei from fresh NR tissue. Published evidence indicates that the chick delta 1 crystallin gene encodes the major structural protein of embryonic lens fibres, whereas the closely related delta 2 gene may encode the urea-cycle enzyme argininosuccinate lyase (ASL). Our present data lends further support to this view. Both immunodetectable delta-related protein(s) and ASL activity are present in fresh embryonic NR tissue, as well as in mouse and Rana liver, and in Rana lens. Our polyclonal anti-delta antibody also cross-reacts with a major constituent of commercial bovine ASL, of the same molecular size as chick delta crystallin. Immunoselection studies suggest that the ASL activity in chick embryonic NR is conferred mainly by the delta-related protein band. So-called 'ectopic' expression of delta crystallin in embryonic NR (and other tissues) may thus involve the delta 2/ASL gene, and could reflect some metabolic requirement for ASL activity.

Animals↗
PubMed1993

Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice.

We have identified a model system for the study of pancreatic islet development and regeneration in transgenic mice bearing the interferon-gamma (IFN-g) gene expressed in the pancreatic islets. Previous studies showed that the locally produced IFN-g causes lymphocyte infiltration and islet cell destruction. Here we demonstrate that new islet cells are formed continuously from duct cells as evidenced by (1) the dramatic proliferation of duct cells, (2) the appearance of primitive cells and (3) their subsequent differentiation to endocrine cells. The IFN-g induced islet neogenesis is similar to embryonic islet morphogenesis and offers a model system for studying factors modulating islet development. Additionally, the duct cells occasionally transdifferentiate to gastrointestinal-like cell types and hepatocytes. These results underscore the lymphokine's ability to initiate a complex 'transdifferentiation' pathway, providing a window for understanding lineage interrelationships within a terminally differentiated structure.

Animals↗