Prevention of osteoporosis and hypogonadism by allogeneic ovarian transplantation in conjunction with intra-bone marrow-bone marrow transplantation.

BACKGROUND: We investigated the effects of ovarian allograft in conjunction with intra-bone marrow-bone marrow transplantation (IBM-BMT) on estrogen deficiency in mice. METHODS: Female C57BL/6 mice underwent ovariectomy (OvX). After 3 months, the mice were irradiated at 9.5 Gy, and the bone marrow cells (BMCs) of female BALB/c mice (8 weeks old) were then injected into the bone cavity of the B6 mice. Simultaneously, allogeneic ovaries from BALB/c mice were transplanted under the renal capsules of the B6 mice. RESULTS: Three months after the transplantation, the hematolymphoid cells were found to be completely reconstituted with donor-derived cells. The transplanted ovary tissues under the renal capsules were accepted without using immunosuppressants; there were a large number of growing follicles at different stages of development. Atrophic endometrium and its glands were also recovered by ovarian transplantation (OT). The transplanted allogeneic ovaries secreted estrogen at normal levels. Furthermore, bone loss was prevented to a certain extent. CONCLUSIONS: These findings suggest that IBM-BMT+OT will become a valuable strategy for young women with malignant tumors to prevent premature senescence, including hypogonadism and osteoporosis, after radiochemotherapy.

Antiplatelet antibody may cause delayed transfusion-related acute lung injury.

A 61-year-old woman with lung cancer developed delayed transfusion-related acute lung injury (TRALI) syndrome after transfusion of plasma- and leukoreduced red blood cells (RBCs) for gastrointestinal bleeding due to intestinal metastasis. Acute lung injury (ALI) recurred 31 days after the first ALI episode. Both ALI episodes occurred 48 hours after transfusion. Laboratory examinations revealed the presence of various antileukocyte antibodies including antiplatelet antibody in the recipient's serum but not in the donors' serum. The authors speculate that antiplatelet antibodies can have an inhibitory effect in the recipient, which can modulate the bona fide procedure of ALI and lead to a delay in the onset of ALI. This case illustrates the crucial role of a recipient's platelets in the development of TRALI.

Transformation potential of bone marrow stromal cells into undifferentiated high-grade pleomorphic sarcoma.

PURPOSE: Bone marrow adherent cells contain conventional bone marrow stromal cells and mesenchymal stem cells and these cells constitute the hematopoietic microenvironment. Mesenchymal stem cells have the capacity to give rise to multiple mesenchymal lineage cells and even ectodermal lineage cells. In the present study, we investigated what types of tumor cells are inducible from BM adherent cells by chemical carcinogens. METHODS: Bone marrow cells from neonatal C3H/HeN mice were collected within 24 h after birth and then cultured. Four days later, bone marrow adherent cells were obtained and the cells were treated with 3-methylcholanthrene. RESULTS: By this treatment, some transformed clones consisting of large spindle cells were obtained. The transformed cells were highly positive for CD44 and were positive for Sca-1, CD49d and CD106, whereas the cells were negative for hematolymphoid markers. The cell clones had the ability to support hematopoiesis in vitro. These results indicate that the transformed cell lines have the characteristics of BM stromal cells/mesenchymal stem cells. Moreover, during culture of the transformed cells, spontaneous bone nodule formation was observed. When the transformed cells were inoculated into immunodeficient mice subcutaneously, the neoplasms grew in the subcutaneous tissue of the mice. Microscopically and ultrastructurally, the neoplasms showed the typical morphology of undifferentiated high-grade pleomorphic sarcoma (UHGPS). Bone-related genes have been found to be expressed in both transformed cells and UHGPSs. CONCLUSION: The present study suggests that UHGPSs are derived from BM stromal cells, probably mesenchymal stem cells.

Contribution of neural cell adhesion molecule (NCAM) to hemopoietic system in monkeys.

Neural cell adhesion molecules (CD56) are important adhesion molecules that are mainly expressed on neural cells and natural killer cells. Although freshly isolated cynomolgus monkey bone marrow cells (BMCs) contained only a few CD56-positive cells, almost all the BM adherent cells (obtained after a 2- to 3-week culture of the BMCs) were stained positively with anti-CD56 monoclonal antibody (mAb). The BM adherent cells showed uniformly fibroblastic morphology and were negative for hematolymphoid markers (CD4, CD8, CD11b, CD14, CD34, and CD45). Adipogenesis and osteogenesis were observed under inductive culture conditions. The BM adherent cells had the ability to support hemopoiesis of hemopoietic stem cells (HSCs) in vitro, and the proliferation of HSCs was significantly inhibited by the addition of anti-CD56 mAb to the coculture system. CD56 molecules were also expressed on HSCs because about 20% of an HSC-enriched population (lineage-negative and blast-gated cells) was positive for CD56. In addition, the immunostaining of monkey BM sections revealed that many stromal cells were CD56-positive, and some CD56-positive stromal cells came into direct contact with CD56-positive hemopoietic cells. These results indicate that the CD56 molecule is expressed on both HSCs and BM stromal cells (containing MSCs) in monkeys, and therefore it can be speculated that CD56 also contributes to the human hematopoietic system.

Extensive studies on perfusion method plus intra-bone marrow-bone marrow transplantation using cynomolgus monkeys.

The collection of bone marrow cells (BMCs) using a perfusion method has been advantageous not only because of the low contamination of BMCs with T cells from the peripheral blood but also the enrichment of stromal cells, which support hemopoiesis. Before the application of this new method to humans, its safety needed to be confirmed using cynomolgus monkeys. We therefore performed the perfusion method on more than 100 cynomolgus monkeys using the long bones (such as the humerus and femur) and also the iliac bones (for human application); in the more than 150 trials to date, there have been no accidental deaths. Furthermore, the technical safety of a new method for the intra-bone marrow (IBM) injection of BMCs (termed IBM-bone marrow transplantation) has also been confirmed using 30 monkeys. Disclosure of potential conflicts of interest is found at the end of this article.

Hepatocellular carcinoma with osteoclast-like giant cells: possibility of osteoclastogenesis by hepatocyte-derived cells.

Giant cell tumor (GCT) of bone is a primary osteolytic tumor that is characterized by the formation of osteoclast-like giant cells. In addition to GCT of bone, extraskeletal GCT are known to be formed in several soft tissues. Giant cells in GCT of bone were suggested to be identical to osteoclasts, but the characterization of giant cells in extraskeletal GCT remains incomplete. In this study, a case of sarcomatoid hepatocellular carcinoma with osteoclast-like giant cells was analyzed. Immunohistochemistry revealed the expression of almost all markers of osteoclasts: tartrate-resistant acid phosphatase, CD68, CD51, CD54 and matrix metalloprotease-9, in osteoclast-like giant cells in the tumor. In situ hybridization revealed the expression of receptor activator of nuclear factor-kappa B (RANK) in the giant cells and receptor activator of nuclear factor-kappa B ligand (RANKL) in the tumor cells. The hepatic origin of the sarcomatoid hepatocellular carcinoma cells was confirmed by the expression of albumin. This is the first report suggesting that hepatocyte-derived cells possess the potential for osteoclastogenesis. In addition, these findings suggest that osteoclast-like cells in the hepatocellular carcinoma were formed by the same mechanism as osteoclastogenesis in bone.