Biomedical subjects
Publications and source records attributed to S Heimfeld.
Mouse bone marrow hematopoietic stem cells were isolated with the use of a variety of phenotypic markers. These cells can proliferate and differentiate with approximately unit efficiency into myelomonocytic cells, B cells, or T cells. Thirty of these cells are sufficient to save 50 percent of lethally irradiated mice, and to reconstitute all blood cell types in the survivors.
Two-color FACS analysis of mouse bone marrow reveals a rare population, comprising 0.1-0.3% of the total, that expresses low levels of the Thy-1 antigen but does not express any of five surface markers that characterize differentiated hematolymphoid cells. We demonstrate here that this fraction of mouse bone marrow is enormously enriched in cells that can home to the thymus and differentiate into mature T lymphocytes, subsequently migrating to peripheral lymphoid organs. Only a subset of the FACS-isolated fraction (1/90 after intrathymic injection) is capable of responding to the thymic microenvironment with a productive commitment to the T cell lineage. A second fraction of mouse bone marrow, which expresses how levels of Thy-1 but is also positive for at least one of five hematolymphoid lineage-specific markers, also contains cells that home to the thymus and establish colonies of thymocytes. The two fractions each contribute approximately equal amounts of thymic colony-forming units (CFUt) to the bone marrow, and together can account for at least half of the CFUt in whole bone marrow.
Due to the tissue dynamics of hydra, every neuron is constantly changing its location within the animal. At the same time specific subsets of neurons defined by morphological or immunological criteria maintain their particular spatial distributions, suggesting that neurons switch their phenotype as they change their location. A position-dependent switch in neuropeptide expression has been demonstrated. The possibility that ganglion cells of the body column are converted into epidermal sensory cells of the head was examined using a monoclonal antibody, TS33, whose binding is restricted to a subset of epidermal sensory cells of the hypostome, the apical end of the head. When animals devoid of interstitial cells, which are the nerve cell precursors, were decapitated and allowed to regenerate, they formed TS33+ epidermal sensory cells. As this latter cell type is not found in the body column, and the interstitial cell-free animals contained only epithelial cells and ganglion cells in the part of the ectoderm that formed the head during regeneration, the TS33+ epidermal sensory cells most likely arose from the TS33- ganglion cells. The observation of epidermal sensory cells labeled with both TS33 and TS26, a monoclonal antibody that binds to ganglion cells, in regenerating and normal heads provides further support. The double-labeled cells are probably in transition from a ganglion cell to an epidermal sensory cell. These results provide a second example of position-dependent changes in neuron phenotype, and suggest that the differentiated state of a neuron in hydra is only metastable with regard to phenotype.
The origin of the gland cells in asexually reproducing adult hydra is unclear. There is evidence suggesting that the gland cells are a self-renewing population as well as contrary evidence suggesting that they must arise from another cell type. We have reexamined the question and found the latter to be the case. Analysis of ectoderm/endoderm chimeras in which the ectoderm was labeled with [3H]thymidine indicates a precursor for gland cells in the ectoderm which migrates into the endoderm. Analysis of grafts between labeled lower halves and unlabeled upper halves of animals indicates the migratory precursor is either a large or a small interstitial cell. Measurement of the cell cycle times of the gland cells and the epithelial cells provided further support. The cell cycle time of the gland cells appears to be longer than that of the epithelial cells of the endoderm throughout the animal. This means that in the steady-state growth condition of hydra tissue, the gland cells cannot maintain their population size simply by cell division. These results and other data suggest the following dynamics for the gland cell population. Gland cells arise by differentiation from large interstitial cells, undergo a limited number of cell divisions, and then become postmitotic.
The interstitial cells of hydra contain a stem cell population which produces several classes of differentiated cell types. A model has been proposed which governs the growth rate of the interstitial cell population. This model, based on the density of interstitial cells in the tissue, makes specific predictions about the relationships among this density, the proportion of stem cells in the interstitial cell population, the growth rate of the interstitial cell population, and the amount of nematocyte differentiation. Hydroxyurea treatments were used to experimentally reduce interstitial cell numbers, and the validity of these expected correlations was tested. The results demonstrate that the predictions of the interstitial cell density model were not upheld. Furthermore, the findings suggest that the interstitial cells are a heterogeneous population, containing some cells which are no longer stem cells but which do retain a limited capacity for proliferation. In the following paper (S. Heimfeld and H.R. Bode, 1986, Dev. Biol. 115, 59-68) we have proposed an alternative mechanism to explain the observed correlations, which incorporates this heterogeneity into amplification divisions of interstitial cells already committed to differentiation.
The precursors for several differentiated cell types in hydra, such as nerve cells and nematocytes, arise from the interstitial cell population. Previously, it has been suggested that the interstitial cells represent a homogeneous stem cell population, and that both the rate of growth and the amount of differentiation are regulated strictly at the level of stem cell self-renewal and commitment. However, recent evidence does not support this viewpoint. In this paper we have proposed that the interstitial cell population is complex, containing both clonable stem cells and other cells which have a reduced division capacity. In response to hydroxyurea treatment, there is an amplification in the number of divisions that the non-stem interstitial cells undergo before differentiating. This amplification model is consistent with the correlations found in the preceding report (S. Heimfeld and H.R. Bode, 1986, Dev. Biol. 115, 51-58) and fits well with previously published data. An additional experiment which tests two specific predictions of this new model is presented.
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The interstitial cells of hydra form a multipotent stem cell system, producing terminally differentiated nerve cells and nematocytes during asexual growth. Under well-fed conditions the interstitial cell population doubles in size every 4 days. We have investigated the possible role of nerve cells in regulating this behavior. Nerve cells are normally found in highest concentrations in the head region of hydra, while interstitial cells are primarily located in the body column. Our experimental approach was to construct, by grafting, animals in which the density of nerve cells varied in (1) the head region, or (2) the body column. The growth of the interstitial cell population was then measured in these hydra. The results indicate that differences in head nerve cell density are closely correlated with how fast the interstitial cell population increases in size. Variations in the level of either nerve cells or interstitial cells in the body column showed no such correlation. These findings suggest the existence of a signaling mechanism in the head region. This signal, which is a function of the density of head nerve cells, emanates from the head tissue and exerts global control on the growth of the interstitial cell population in the body column.
The interstitial cells of hydra comprise a stem cell population, producing at least two classes of terminally differentiated cell types, nerve cells and nematocytes. Exposure to hydroxyurea (HU) results in selective depletion of interstitial cells from the tissue. The surviving cells subsequently recovered to normal levels, and the mechanisms involved in this repopulation were examined. Hydra were treated for varying times with HU such that interstitial cell numbers were reduced to 7 or 35% of normal. Subsequent growth of the epithelial and interstitial cell populations in these animals was monitored. The results indicate that the growth rates of these two cell types were only slightly different from untreated controls during the 4 weeks after HU exposure, implying that repopulation should not have occurred. However, recovery of the interstitial cell population was observed. Further analysis revealed that the interstitial cells in HU animals, unlike normal hydra, were not uniformly distributed in the body column, and were especially reduced in the budding region. In normal animals a constant fraction of the interstitial and epithelial cells are lost into buds. However, as a consequence of this nonuniform distribution a smaller fraction of the interstitial cells are displaced into HU buds, thereby retaining a higher proportion in the adult tissue. Calculations indicate that this mechanism of increased retention is of sufficient magnitude to account for 40-60% of the observed recovery after HU treatment.
The interstitial cell system of hydra contains multipotent stem cells which can form at least two classes of differentiated cell types, nerves and nematocytes. The amount of nerve and nematocyte production varies in an axially dependent pattern along the body column. Some interstitial cells can migrate, which makes it conceivable that this observed pattern of differentiation is not the result of regionally specified stem cell commitment, but rather arises by the selective movement of predetermined cells to the correct site prior to expression. To assess this latter possibility quantitative information on the dynamics of interstitial cell migration was obtained. Epithelial hydra were grafted to normal animals in order to measure (1) the number of cells migrating per day, (2) the location of these cells within the host tissue, and (3) the axial directionality of this movement. Tissue properties such as axial position and the density of cells within the interstitial spaces of the host were also tested for their possible influence on migration. Results indicate that there is a considerable traffic of migrating interstitial cells and this movement has many of the characteristics necessary to generate the position-dependent pattern of nerve differentiation.
In Hydra, the interstitial cells constitute a multipotent stem cell system, forming nerve cells and nematocytes. Differentiation of these product cells varies in an axially dependent manner along the body column, and either of two simple hypotheses can explain this phenomena: (1) position-dependent stem cell determination or (2) selective migration of committed precursor cells. This latter hypothesis predicts that the migrating interstitial cell population is enriched with cells which are restricted in their proliferation and differentiation potential. To test this idea several developmental properties of the migrating cells were compared with those of the total interstitial cell population. The results indicate that those interstitial cells that migrate are not a random sample of the whole population. They contain a lower proportion of stem cells, as shown both by a slower growth rate and by a reduced capacity for clone formation. The migrating population is specifically enriched with interstitial cells that are committed to nerve differentiation. Coupled with previous measurements on migration rates, these findings suggest that the observed position-dependent pattern of nerve differentiation results from the selective redistribution of committed nerve cell precursors.
The interstitial cell of hydra is a multipotent stem cell, which produces nerve cells as one of its differentiated cell types. The amount of interstitial cell commitment to nerve differentiation varies in an axially dependent pattern along the body column. The distribution of nerve cell density has the same equivalent axial pattern. These facts have led to speculation that the regulation of nerve cell commitment is dictated by the nerve cell density. We examined this question by assaying interstitial cell commitment behaviour in 2 cases where the normal nerve cell density of the tissue had been perturbed: (1) in epithelial hydra in which no nerve cells were present; and (2) in hydra derived from regenerating-tip isolates in which the nerve density was increased nearly 4-fold. We found no evidence of regulation of nerve cell commitment in response to the abnormal nerve cell densities. However, the typical axial pattern of nerve commitment was still obtained in both sets of experiments, which suggests that interstitial cell commitment to nerve differentiation is dependent on some parameter of axial location that is not associated directly with the local nerve cell density.
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