17 results on '"Weilbaecher, K N"'
Search Results
2. The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects
- Author
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Hurchla, M A, Garcia-Gomez, A, Hornick, M C, Ocio, E M, Li, A, Blanco, J F, Collins, L, Kirk, C J, Piwnica-Worms, D, Vij, R, Tomasson, M H, Pandiella, A, San Miguel, J F, Garayoa, M, and Weilbaecher, K N
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- 2013
- Full Text
- View/download PDF
3. Multiple facets of junD gene expression are atypical among AP-1 family members
- Author
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Hernandez, J M, Floyd, D H, Weilbaecher, K N, Green, P L, and Boris-Lawrie, K
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- 2008
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4. The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling
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Su, X., Floyd, D. H., Hughes, A., Xiang, J., Schneider, Jochen, Uluckan, O., Heller, E., Deng, H., Zou, W., Craft, C. S., Wu, K., Hirbe, A. C., Grabowska, D., Eagleton, M. C., Townsley, S., Collins, L., Piwnica-Worms, D., Steinberg, T. H., Novack, D. V., Conley, P. B., Hurchla, M. A., Rogers, M., Weilbaecher, K. N., and Luxembourg Centre for Systems Biomedicine (LCSB): Medical Translational Research (J. Schneider Group) [research center]
- Subjects
Endocrinology, metabolism & nutrition [D06] [Human health sciences] ,Cardiovascular & respiratory systems [D03] [Human health sciences] ,Systèmes cardiovasculaire & respiratoire [D03] [Sciences de la santé humaine] ,Endocrinologie, métabolisme & nutrition [D06] [Sciences de la santé humaine] - Abstract
The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss.
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- 2012
5. Integrins and bone metastasis: integrating tumor cell and stromal cell interactions
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Schneider, Jochen, Amend, S. R., Weilbaecher, K. N., and Luxembourg Centre for Systems Biomedicine (LCSB): Medical Translational Research (J. Schneider Group) [research center]
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Platelets ,Integrins ,Cancer therapy ,Endocrinology, metabolism & nutrition [D06] [Human health sciences] ,Osteoclasts ,Bone metastasis ,Endothelium ,Cardiovascular & respiratory systems [D03] [Human health sciences] ,Systèmes cardiovasculaire & respiratoire [D03] [Sciences de la santé humaine] ,Endocrinologie, métabolisme & nutrition [D06] [Sciences de la santé humaine] - Abstract
Integrins on both tumor cells and the supporting host stromal cells in bone (osteoclasts, new blood vessels, inflammatory cells, platelets and bone marrow stromal cells) play key roles in enhancing bone metastasis. Tumor cells localize to specific tissues through integrin-mediated contacts with extracellular matrix and stromal cells. Integrin expression and signaling are perturbed in cancer cells, allowing them to "escape" from cell-cell and cell-matrix tethers, invade, migrate and colonize within new tissues and matrices. Integrin signaling through αvβ3 and VLA-4 on tumor cells can promote tumor metastasis to and proliferation in the bone microenvironment. Osteoclast (OC) mediated bone resorption is a critical component of bone metastasis and can promote tumor growth in bone and αvβ3 integrins are critical to OC function and development. Tumors in the bone microenvironment can recruit new blood vessel formation, platelets, pro-tumor immune cells and bone marrow stromal cells that promote tumor growth and invasion in bone. Integrins and their ligands play critical roles in platelet aggregation (αvβ3 and αIIbβ3), hematopoietic cell mobilization (VLA-4 and osteopontin), neoangiogenesis (αvβ3, αvβ5, α6β4, and β1 integrin) and stromal function (osteopontin and VLA-4). Integrins are involved in the pathogenesis of bone metastasis at many levels and further study to define integrin dysregulation by cancer will yield new therapeutic targets for the prevention and treatment of bone metastasis.
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- 2011
6. Microphthalmia transcription factor: a sensitive and specific marker for malignant melanoma in cytologic specimens.
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Dorvault, C C, Weilbaecher, K N, Yee, H, Fisher, D E, Chiriboga, L A, Xu, Y, and Chhieng, D C
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- 2001
7. The CXCR4/SDF-1 chemokine axis: a potential therapeutic target for bone metastases?
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Hirbe AC, Morgan EA, and Weilbaecher KN
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- Animals, Bone Neoplasms complications, Bone Resorption etiology, Breast Neoplasms pathology, Chemokines, CXC antagonists & inhibitors, Chemokines, CXC metabolism, Female, Humans, Male, Mice, Models, Biological, Prostatic Neoplasms pathology, Receptors, CXCR4 genetics, Bone Neoplasms drug therapy, Bone Neoplasms secondary, Chemokine CXCL12 antagonists & inhibitors, Chemokine CXCL12 metabolism, Receptors, CXCR4 antagonists & inhibitors, Receptors, CXCR4 metabolism
- Abstract
Chemokines and chemokine receptors play diverse roles in homeostasis. The chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 have critical functions in the immune, circulatory, and central nervous systems and have also been implicated in tumor biology and metastasis. Here we review the current data regarding the role of the CXCR4/SDF-1 chemokine axis in the development of bone metastases, derived from tumor models of breast or prostate cancers. There is substantial evidence that CXCR4 and SDF-1 directly influence the survival and proliferation of tumor cells. In regards to bone metastases, the CXCR4/SDF-1 axis also appears to facilitate tumor cell recruitment to the bone marrow microenvironment via a homing mechanism. This makes disruption of the chemokine axis an attractive therapeutic target for the prevention of tumor cell spread to bone. However, within the bone microenvironment, SDF-1 and CXCR4 appear to have conflicting roles. While genetic disruption of CXCR4 enhances osteoclast activity and therefore stimulates tumor cell growth in the bone - likely via release of bone-derived growth factors - SDF-1 has been shown to have either a stimulatory effect or no effect on osteoclasts. In short, the effects of the CXCR4/SDF-1 axis on tumor cell growth within the bone are not yet fully defined. Further, there are theoretical risks that blockade of this chemokine axis could impair immune function or mobilize tumor cells leading to other sites of metastasis. As such, caution should be taken when designing therapeutic strategies targeting this chemokine axis.
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- 2010
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8. Linkage of M-CSF signaling to Mitf, TFE3, and the osteoclast defect in Mitf(mi/mi) mice.
- Author
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Weilbaecher KN, Motyckova G, Huber WE, Takemoto CM, Hemesath TJ, Xu Y, Hershey CL, Dowland NR, Wells AG, and Fisher DE
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- Amino Acid Motifs, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Differentiation physiology, Cells, Cultured, DNA-Binding Proteins genetics, Green Fluorescent Proteins, Humans, Immunohistochemistry, Indicators and Reagents metabolism, Luminescent Proteins metabolism, Macrophage Colony-Stimulating Factor metabolism, Macrophages cytology, Macrophages drug effects, Macrophages metabolism, Mice, Mice, Inbred Strains, Microphthalmia-Associated Transcription Factor, Mitogen-Activated Protein Kinases metabolism, Osteoclasts cytology, Osteoclasts drug effects, Osteopetrosis physiopathology, Phosphorylation, DNA-Binding Proteins metabolism, MAP Kinase Signaling System physiology, Macrophage Colony-Stimulating Factor pharmacology, Osteoclasts physiology, Transcription Factors metabolism
- Abstract
Osteoclasts are multinucleated hematopoietic cells essential for bone resorption. Macrophage colony-stimulating factor (M-CSF) is critical for osteoclast development and function, although its nuclear targets in osteoclasts are largely unknown. Mitf and TFE3 are two closely related helix-loop-helix (HLH) transcription factors previously implicated in osteoclast development and function. We demonstrate that cultured Mitf(mi/mi) osteoclasts are immature, mononuclear, express low levels of TRAP, and fail to mature upon M-CSF stimulation. In addition, M-CSF induces phosphorylation of Mitf and TFE3 via a conserved MAPK consensus site, thereby triggering their recruitment of the coactivator p300. Furthermore, an unphosphorylatable mutant at the MAPK consensus serine is specifically deficient in formation of multinucleated osteoclasts, mimicking the defect in Mitf(mi/mi) mice. These results identify a signaling pathway that appears to coordinate cytokine signaling with the expression of genes vital to osteoclast development.
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- 2001
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9. Microphthalmia transcription factor: not a sensitive or specific marker for the diagnosis of desmoplastic melanoma and spindle cell (non-desmoplastic) melanoma.
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Granter SR, Weilbaecher KN, Quigley C, Fletcher CD, and Fisher DE
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- Adult, Aged, Aged, 80 and over, Antigens, Neoplasm, Female, Humans, Immunohistochemistry, MART-1 Antigen, Male, Melanoma chemistry, Melanoma pathology, Melanoma-Specific Antigens, Microphthalmia-Associated Transcription Factor, Middle Aged, S100 Proteins analysis, Sensitivity and Specificity, Skin Neoplasms chemistry, Skin Neoplasms pathology, Biomarkers, Tumor analysis, DNA-Binding Proteins analysis, Melanoma diagnosis, Neoplasm Proteins analysis, Skin Neoplasms diagnosis, Transcription Factors analysis
- Abstract
Microphthalmia transcription factor (Mitf), a melanocytic nuclear protein critical for the embryonic development and postnatal viability of melanocytes, is a master lineage regulator and modulates extracellular signals. Recently, Mitf expression was shown to be both a sensitive and specific marker of epithelioid melanoma. Because loss of specific melanocytic markers in melanomas with spindle cell morphology is more common compared with those tumors with epithelioid morphology, we investigated the sensitivity of D5, an anti-Mitf antibody, for diagnosis in this diagnostically problematic subset of melanomas. Twenty of 21 (95%) spindle cell and desmoplastic melanomas examined were reactive for S-100 protein. Only 4 of 21 (19%) spindle cell and desmoplastic melanomas were reactive for HMB-45. Six of 21 tumors (29%) were reactive for D5, including one case that was non-reactive for S-100 and HMB-45. Melan-A reactivity was seen in 2 of 13 cases (15%) studied. Eight of 24 (33%) non-melanocytic spindle cell tumors were reactive for D5, including 4 of 6 dermatofibromas, 1 of 6 schwannomas, 1 of 2 leiomyomas, and 2 of 6 leiomyosarcomas. Although D5 was shown in a previous study to be a highly sensitive and specific marker for epithelioid melanomas, the results of this study show it is not a sensitive or specific marker of spindle cell and desmoplastic melanomas. Nevertheless, we believe that diffuse positive staining for D5 when taken in clinical, histologic and immunohistochemical context may be diagnostically useful in selected cases of melanoma.
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- 2001
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10. Clear cell sarcoma shows immunoreactivity for microphthalmia transcription factor: further evidence for melanocytic differentiation.
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Granter SR, Weilbaecher KN, Quigley C, Fletcher CD, and Fisher DE
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- Adolescent, Adult, Biomarkers, Tumor metabolism, Cell Differentiation, Child, Female, Fluorescent Antibody Technique, Direct, Humans, Male, Melanocytes immunology, Microphthalmia-Associated Transcription Factor, Middle Aged, Neoplasm Proteins metabolism, Sarcoma, Clear Cell pathology, Sensitivity and Specificity, Soft Tissue Neoplasms pathology, DNA-Binding Proteins biosynthesis, Melanocytes metabolism, Sarcoma, Clear Cell metabolism, Soft Tissue Neoplasms metabolism, Transcription Factors biosynthesis
- Abstract
Microphthalmia transcription factor, a melanocytic nuclear protein critical for the embryonic development and postnatal viability of melanocytes, is a master regulator in modulating extracellular signals. Recently, microphthalmia transcription factor expression was shown to be both a sensitive and specific marker of epithelioid melanoma. We investigated the sensitivity of D5, an anti-microphthalmia transcription factor antibody, for diagnosis of clear cell sarcoma (also known as malignant melanoma of soft parts). Immunoreactivity in a nuclear pattern for D5 was present in 8 of 12 (75%) tumors. D5 staining was strong in three tumors, moderate in two, and weak in three. S-100 protein expression was seen in all 12 cases that had clear cell sarcoma examined. HMB-45 staining was seen in 11 of 12 (92%) tumors. Focal Melan-A positivity was seen in 3 of 7 (43%) tumors. Although D5 was shown in a previous study to be a highly sensitive and specific marker for epithelioid melanomas, the results of this study expand the spectrum of tumors showing immunoreactivity for D5. D5 immunoreactivity in clear cell sarcoma provides further evidence for melanocytic differentiation in this unusual tumor.
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- 2001
- Full Text
- View/download PDF
11. Microphthalmia transcription factor expression in cutaneous benign, malignant melanocytic, and nonmelanocytic tumors.
- Author
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King R, Googe PB, Weilbaecher KN, Mihm MC Jr, and Fisher DE
- Subjects
- Antigens, Neoplasm, Humans, Immunohistochemistry, Melanoma-Specific Antigens, Microphthalmia-Associated Transcription Factor, S100 Proteins analysis, Sensitivity and Specificity, DNA-Binding Proteins analysis, Melanocytes chemistry, Melanoma chemistry, Neoplasm Proteins analysis, Nevus chemistry, Skin Neoplasms chemistry, Transcription Factors
- Abstract
The protein encoded by the microphthalmia (mi) gene is a transcription factor essential for the development and survival of melanocytes. Using a monoclonal antibody generated against human Mi transcription factor protein (Mitf) the authors previously demonstrated that Mitf expression is conserved in primary and metastatic malignant melanomas, and appears to be a highly sensitive and specific melanocytic marker. Mitf expression in various cutaneous nevi and cutaneous nonmelanocytic tumors has not been documented systematically. The authors evaluated Mitf immunostaining in 62 benign nevi, 58 primary cutaneous melanomas, and 53 nonmelanocytic tumors. Mitf immunostaining was conserved in all benign nevi, with Spitz nevi and neurotized nevi demonstrating decreased staining intensity. With the exception of desmoplastic melanomas, all primary cutaneous melanomas were immunopositive regardless of the cell type. Only one of 14 desmoplastic melanomas was Mitf positive. None of the nonmelanocytic tumors was immunopositive, including those lesions that may resemble melanoma histologically (spindle cell carcinomas, atypical fibroxanthomas, and leiomyosarcomas). The results demonstrate that Mitf antibody expression is conserved in the majority of benign and malignant melanocytic lesions, and that it may be helpful in the diagnosis of primary melanocytic skin lesions. Its use in desmoplastic melanomas is limited and is reflective of other melanocyte-associated antigens. Mitf discriminates between spindle cell nonmelanocytic tumors and melanomas with a spindle cell morphology, and is useful in a panel with other appropriate antibodies.
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- 2001
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12. Mechanisms of osteoporosis after hematopoietic cell transplantation.
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Weilbaecher KN
- Subjects
- Bone Remodeling drug effects, Bone Remodeling physiology, Bone Remodeling radiation effects, Combined Modality Therapy adverse effects, Hormones adverse effects, Hormones therapeutic use, Humans, Immunosuppressive Agents adverse effects, Immunosuppressive Agents therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects, Osteoporosis etiology, Osteoporosis metabolism
- Abstract
Osteopenia and osteoporosis are common complications of bone marrow and peripheral blood stem cell transplantation. Bone loss occurs in 50% to 60% of patients treated with the most common preparatory regimens. The major causes of transplant-related bone loss are primary hypogonadism (low estrogen and testosterone), secondary hyperparathyroidism due to low serum calcium, and posttransplant steroid therapy. Other transplant-related treatments that induce bone loss are discussed. Trabecular bone is particularly vulnerable to transplant-related therapies. The spine and hip contain 50% to 75% trabecular bone and are most at risk for fracture after hematopoietic cell transplantation (HCT). The structure of bone and the bone cells that are involved in maintaining skeletal integrity are discussed, followed by a discussion of the transplant-related therapies that have been shown to cause damage to bone and lead to bone loss. Recommendations for patients undergoing HCT include (1) evaluation of bone mineral density either shortly before or shortly after transplantation and appropriate intervention and monitoring based on the results; and (2) evaluation of estrogen and testosterone levels after HCT and replacement when appropriate; and (3) administration of bisphosphonate therapy to all patients on steroids for >2 months. Early intervention and prevention of bone loss can have a tremendous clinical impact for patients undergoing HCT because once significant bone loss has occurred, it is difficult to reverse.
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- 2000
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13. Microphthalmia transcription factor. A sensitive and specific melanocyte marker for MelanomaDiagnosis.
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King R, Weilbaecher KN, McGill G, Cooley E, Mihm M, and Fisher DE
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- Animals, Antigens, Neoplasm metabolism, Biomarkers, Tumor biosynthesis, Blotting, Western, Cell Line, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Melanoma diagnosis, Melanoma-Specific Antigens, Mice, Microphthalmia-Associated Transcription Factor, Neoplasm Proteins metabolism, Nevus metabolism, Reverse Transcriptase Polymerase Chain Reaction, S100 Proteins metabolism, Sensitivity and Specificity, Skin Neoplasms diagnosis, Transcription Factors biosynthesis, DNA-Binding Proteins biosynthesis, Melanocytes metabolism, Melanoma metabolism, Skin Neoplasms metabolism
- Abstract
Malignant melanomas do not uniformly retain expression of melanocytic gene products-an observation associated with diagnostic dilemmas. Microphthalmia transcription factor (Mitf) is a melanocytic nuclear protein critical for the embryonic development and postnatal viability of melanocytes. It serves as a master regulator in modulating extracellular signals, such as those triggered by alpha-MSH and c-Kit ligand. Because of its central role in melanocyte survival and to assess its potential use as a histopathological marker for melanoma, Mitf expression was examined in histologically confirmed human melanoma specimens. Western blot analysis of melanoma cell lines revealed consistent expression of two Mitf protein isoforms differing by MAP kinase-mediated phosphorylation. In a series of 76 consecutive human melanoma surgical specimens, 100% stained positively for Mitf with a nuclear pattern of reactivity. In a side-by-side comparison, Mitf staining was positive in melanomas that failed to stain for either HMB-45 or S-100, the most common currently used melanoma markers. Of 60 non-melanoma tumors, none displayed nuclear Mitf staining and two displayed cytoplasmic staining. Although Mitf does not distinguish benign from malignant melanocytic lesions, for invasive neoplasms it appears to be a highly sensitive and specific histopathological melanocyte marker for melanoma.
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- 1999
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14. alpha-Melanocyte-stimulating hormone signaling regulates expression of microphthalmia, a gene deficient in Waardenburg syndrome.
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Price ER, Horstmann MA, Wells AG, Weilbaecher KN, Takemoto CM, Landis MW, and Fisher DE
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- Animals, Cell Line, Cricetinae, Cyclic AMP metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Humans, Microphthalmia-Associated Transcription Factor, Phosphorylation, Promoter Regions, Genetic, Waardenburg Syndrome metabolism, DNA-Binding Proteins genetics, Gene Expression Regulation, Signal Transduction, Transcription Factors, Waardenburg Syndrome genetics, alpha-MSH metabolism
- Abstract
The pituitary peptide alpha-melanocyte-stimulating hormone (alpha-MSH) stimulates melanocytes to up-regulate cAMP, but the downstream targets of cAMP are not well understood mechanistically. One consequence of alpha-MSH stimulation is increased melanization attributable to induction of pigmentation enzymes, including tyrosinase, which catalyzes a rate-limiting step in melanin synthesis. The tyrosinase promoter is a principle target of the melanocyte transcription factor Microphthalmia (Mi), a factor for which deficiency in humans causes Waardenburg syndrome II. We show here that both alpha-MSH and forskolin, a drug that increases cAMP, stimulate a rapid increase in Mi mRNA and protein levels in both melanoma cell lines and primary melanocytes. This up-regulation requires a cAMP-responsive element within the Mi promoter, and the pathway leading to Mi stimulation is subject to tight homeostatic regulation. Although cAMP signaling is ubiquitous, the Mi promoter was seen to be cAMP-responsive in melanocytes but not in nonmelanocytes. Moreover, dominant negative interference with Mi impeded successful alpha-MSH stimulation of tyrosinase. The regulation of Mi expression via alpha-MSH thus provides a direct mechanistic link to pigmentation. In addition, because the human melanocyte and deafness condition Waardenburg syndrome is sometimes caused by haploinsufficiency of Mi, its modulation by alpha-MSH suggests therapeutic strategies targeted at up-regulating the remaining wild type Mi allele.
- Published
- 1998
- Full Text
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15. Age-resolving osteopetrosis: a rat model implicating microphthalmia and the related transcription factor TFE3.
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Weilbaecher KN, Hershey CL, Takemoto CM, Horstmann MA, Hemesath TJ, Tashjian AH, and Fisher DE
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- Animals, Base Sequence, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Gene Expression, Helix-Loop-Helix Motifs, Humans, Leucine Zippers, Mice, Microphthalmia-Associated Transcription Factor, Molecular Sequence Data, Osteoblasts metabolism, RNA, Messenger genetics, Rats, Rats, Mutant Strains, Sequence Alignment, Sequence Homology, Nucleic Acid, DNA-Binding Proteins genetics, DNA-Binding Proteins physiology, Microphthalmos genetics, Osteoclasts physiology, Osteopetrosis etiology, Transcription Factors physiology
- Abstract
Microphthalmia (Mi) is a basic helix-loop-helix-leucine zipper (b-HLH-ZIP) transcription factor implicated in pigmentation, mast cells, and bone development. Two dominant-negative mi alleles (mi/mi and Mior/Mior) in mice cause osteopetrosis. In contrast, osteopetrosis has not been observed in a number of recessive mi alleles, suggesting the existence of Mi protein partners important in osteoclast function. An osteopetrotic rat of unknown genetic defect (mib) has been described whose skeletal sclerosis improves dramatically with age and that is associated with pigmentation defects reminiscent of mouse mi alleles. Here we report that this rat strain harbors a large genomic deletion encompassing the 3' half of mi including most of the b-HLH-ZIP region. Osteoclasts from these animals lack Mi protein in contrast to wild-type rat, mouse, and human osteoclasts. Mi is not detectable in primary osteoblasts. In addition TFE3, a b-HLH-ZIP transcription factor related to Mi, was found to be expressed in osteoclasts, but not osteoblasts, and to coimmunoprecipitate with Mi. These results demonstrate the existence of members of a family of biochemically related transcription factors that may cooperate to play a central role in osteoclast function and possibly in age-related osteoclast homeostasis.
- Published
- 1998
- Full Text
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16. Porphyria cutanea tarda and hepatitis C virus infection in a patient with acute liver failure.
- Author
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Jasmer RM, Larson MS, and Weilbaecher KN
- Subjects
- Adult, Humans, Male, Hepatitis C complications, Liver Failure, Acute complications, Porphyria Cutanea Tarda complications
- Published
- 1994
17. Long-term human hematopoiesis in the SCID-hu mouse.
- Author
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Namikawa R, Weilbaecher KN, Kaneshima H, Yee EJ, and McCune JM
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- Animals, Fetal Tissue Transplantation, Graft vs Host Disease, Hematopoietic Stem Cells physiology, Humans, Immunologic Deficiency Syndromes physiopathology, Liver Transplantation, Mice, Mice, Mutant Strains, T-Lymphocytes physiology, Thymus Gland transplantation, Hematopoiesis, Immunologic Deficiency Syndromes immunology
- Abstract
Coimplantation of small fragments of human fetal thymus and fetal liver into immunodeficient SCID mice resulted in the formation of a unique structure (Thy/Liv). Thereafter, the SCID-hu mice showed reproducible and long-term reconstitution of human hematopoietic activity. For periods lasting 5-11 mo after transplantation, active T lymphopoiesis was observed inside the grafts and cells that were negative for T cell markers were found to have colony-forming units for granulocyte/macrophage (CFU-GM) and erythroid burst-forming unit (BFU-E) activity in the methylcellulose colony assay. In addition, structures similar to normal human bone marrow were observed inside the Thy/Liv grafts, consisting of blast cells, mature and immature forms of myelomonocytic cells, and megakaryocytes. These data indicate long-term maintenance, in vivo, of human progenitor cells for the T lymphoid, myelomonocytic, erythroid, and megakaryocytic lineages. The role of the implanted fetal liver fragments was analyzed using HLA-mismatched Thy/Liv implants. The HLA type of the liver donor was found on T cells and macrophages in the graft. In addition, cells grown in the methylcellulose colony assay and cells in a bone marrow-like structure, the "thymic isle," expressed the HLA type of the liver donor. Thus, the Thy/Liv implants provided a microenvironment in which to follow human hematopoietic progenitor cells for multiple lineages. The formation of the Thy/Liv structures also results in a continuous source of human T cells in the peripheral circulation of the SCID-hu mouse. Though present for 5-11 mo, these cells did not engage in a xenograft (graft-versus-host) reaction. This animal model, the first in which multilineage human hematopoietic activity is maintained for long periods of time, should be useful for the analysis of human hematopoiesis in vivo.
- Published
- 1990
- Full Text
- View/download PDF
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