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A retrospective study compared posttransplant engraftment parameters in 203 patients with myelofibrosis (MF) with those in a population of 203 matched controls without MF. There were no significant differences between these groups in the proportions of patients who died without achieving engraftment and in the disease-free survival distributions. Furthermore, comparisons between the two groups of patients reaching the respective endpoints showed no differences in the time distributions for reaching 0.5 or 1.0 x 10(9)/L granulocytes, but the time to platelet transfusion independence was 3 days longer in patients with MF. In further analysis, results for 33 patients with severe MF were compared with those of their respective controls. The proportions of patients with severe MF who died without reaching these engraftment endpoints and the disease-free survival distributions in the two groups were similar. Among patients who reached the respective engraftment endpoints, there was no statistically significant difference in the pace of granulocyte recovery. In patients with severe MF, there was a 7-day delay in the time to reach platelet transfusion independence and a 2-day delay in the time to reach red blood cell independence, but the differences were not statistically significant. The present results do not substantiate concerns raised by earlier studies. MF may delay the time to reach platelet independence by approximately 3 days and may increase platelet transfusion requirements, but no other perturbation of hematopoietic reconstitution was apparent.
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Using heterotrophic transplantation of syngenic bone marrow under the renal capsule, the effect of hypokinesia on osteogenic and hemopoietic cells-precursors as well as on de novo formed bone marrow was investigated. Altogether 16 experiments were performed, employing 260 recipients and 200 donors in two modifications: 1) bone marrow from animals exposed to hypokinesia for 3 days or 3 weeks (stage I or II of the general adaptation syndrome) was implanted to intact mice; 2) recipients who 5 to 7 day before exposure were implanted with bone marrow from intact donors were hypokinetic for 3 weeks. It was found that determined bone marrow precursors of osteogenic tissue as well as cells transferring hemopoietic microenvironment remained insensitive to hypokinesia. Three-week hypokinesia produced noticeable inhibition of osteogenesis and hemopoiesis. It is concluded that the stress-reaction plays the leading role in the changes that develop in hypokinetic mice.
Bone marrow stromal cells are multipotential stem cells that contribute to the differentiation of tissues such as bone, cartilage, fat and muscle. In the experiment, we found that bone marrow stromal cells can be induced to differentiate into cells expressing characteristic markers of Schwann cells, such as S-100 and glial fibrillary acidic protein, promoting peripheral nerve regeneration. Tissue-engineered bioartificial nerve grafting of rats by differentiated bone marrow stromal cells was applied for bridging a 10 mm-long sciatic nerve defect. Twenty-eight inbred strains of female F344 rats weighing 160 approximately 200 g were randomly divided into four nerve grafting groups, with seven rats in each group. Differentiated bone marrow stromal cell-laden group: poly(lactic-co-glycolic) acid tubes with an intrinsic framework were seeded with syngeneic bone marrow stromal cells which were induced for 5 days; Schwann cell-laden group: poly(lactic-co-glycolic) acid tubes with an intrinsic framework were seeded with syngeneic Schwann cells; acellular group: poly(lactic-co-glycolic) acid tubes were only filled with an intrinsic framework; autografts group. Three months later, a series of examinations was performed, including electrophysiological methods, walking track analysis, immunohistological staining of nerves, immunostaining of S-100 and neurofilament, and axon counts. The outcome indicated that bone marrow stromal cells are able to differentiate into Schwann-like cells and Schwann-like cells could promote nerve regeneration. Bone marrow stromal cells may be potentially optional seed cells for peripheral nerve tissue engineering because of abilities of promoting axonal regeneration.
We have examined the effects of BMP-2 on the expression of bone matrix proteins in both human bone marrow stromal cells (HBMSC) and human osteoblasts (HOB) and their proliferation and mineralization. Both HBMSC and HOB express BMP-2/-4 type I and type II receptors. Treatment of these two cell types with BMP-2 for 4 weeks in the presence of beta-glycerophosphate and ascorbic acid results in mineralization of their matrix. BMP-2 increases the mRNA level and activities of alkaline phosphatase and elevates the mRNA levels and protein synthesis of osteopontin, bone sialoprotein, osteocalcin, and alpha 1(I) collagen in both cell types. Whereas the mRNA level of decorin is increased, the mRNA concentration of biglycan is not altered by BMP-2. No effect on osteonectin is observed. The effect of BMP-2 on bone matrix protein expression is dose dependent from 25 to 100 ng/ml and is evident after 1-7 days treatment. In the presence of BMP-2, proliferation of HBMSC and HOB is decreased under either serum-free condition or in the presence of serum. Thus, BMP-2 has profound effects on the proliferation, expression of most of the bone matrix proteins and the mineralization of both relatively immature human bone marrow stromal preosteoblasts and mature human osteoblasts.
Two patients with high-grade disseminated non-Hodgkin's lymphoma relapsed 3 and 7 months respectively after high-dose chemotherapy and autologous BMT performed in first complete remission. Both patients had an HLA-identical sibling and received an allogeneic BMT 5 and 10 months after autologous BMT, after conditioning with fractionated 12 Gy total body irradiation plus cyclophosphamide. They both are alive and well, with a Karnofsky score of 100%, 15 and 27 months after allogeneic BMT. For selected patients with HLA-identical siblings and good performance status who relapse after autologous transplantation for high-grade non-Hodgkin's lymphoma, allogeneic BMT may be an option.
Increasing evidence especially stemming from peripheral blood progenitor transplantation studies points to a possible biologic difference between mobilized blood and bone marrow progenitor cells. The objective of this study was to compare the in situ radiation sensitivity of recombinant human granulocyte colony-stimulating factor (rhG-CSF)-recruited circulating granulopoietic (blood colony-forming unit-granulocyte-macrophage [CFU-GM(blood)]) and megakaryocytopoietic (blood CFU-megakaryocyte [CFU-Meg(blood)]) progenitors, with the nonmobilized fraction remaining in the bone marrow (CFU-GM(femur) and CFU-Meg(femur)). Splenectomized male B6D2F1 mice received 50 micrograms/kg/d rhG-CSF daily for 8 days to induce high levels of circulating progenitors, followed by either total body X-irradiation (TBI) or X-irradiation of the chest (CI) with 62.5, 125, 250, or 500 cGy. Progenitor cells were assayed 24 hours after irradiation. Circulating CFU-GM and CFU-Meg in the blood were decreased in a dose-dependent fashion by both TBI and CI, with TBI causing greater damage than CI. Average D0 values for TBI were 53 cGy for CFU-GM(blood) and 40 cGy for CFU-Meg(blood) D0 values for CI were 90 cGy for CFU-GM(blood) and 140 cGy for CFU-Meg(blood). As seen for blood progenitor cells, TBI caused a dose-dependent decrease of both CFU-GM(femur) (D0, 136 cGy) and CFU-Meg(femur) (D0, 148 cGy). However, radiation-induced bone marrow progenitor cell kill was significantly lower when compared with blood progenitors. Despite the fact that circulating blood elements only received a fraction of the total dose administered as Cl, the extent of blood progenitor kill caused by Cl was higher than the effects of identical TBI doses on bone marrow CFU. The results of this study showed that rhG-CSF-recruited CFU-Meg(blood) and CFU-GM(blood) were considerably more radiosensitive than femoral progenitors, thereby providing novel evidence for a biologic difference between rhG-CSF-recruited peripheral blood progenitors and the nonrecruited bone marrow CFU.
Of 95 young patients with non-Hodgkin's lymphoma treated at the National Cancer Institute on Pediatric Branch Protocol 7704, 18 (18.9%) had bone marrow involvement prior to treatment. Their mean age was 20.5 years. Twelve patients had small, non-cleaved lymphoma (ten Burkitt's and two undifferentiated, unspecified), five had lymphoblastic lymphoma, and one had a diffuse large cell lymphoma. All had extensive disease. We obtained bilateral bone marrow biopsy specimens, touch preparations, clot sections, and aspirate smears from 13 of the 18 patients. When paired contralateral samples were reviewed, in as many as six out of ten of the pairs only one side was positive for tumor. When paired ipsilateral samples were similarly reviewed, in as many as seven out of 21 of the pairs only one specimen was positive for tumor. The biopsy specimen was the most useful of the four types of study performed, yielding positive results in 87% of the preparations. Thus, in a high percentage of patients, multiple marrow sampling revealed disease that might have been missed if fewer specimens had been obtained. Only four of our 18 patients (22.2%) had long-term remissions. Because young patients with marrow disease are at high risk and may be eligible for more intensive treatment protocols, we recommend that staging should include bilateral bone marrow biopsies and bilateral aspirates.
This study deals with murine marrow stromal cells (MSC) during hematopoietic regeneration. Regenerative marrow was induced in infant mice by two consecutive i. p. injections of hydroxyurea (HU) (2 X 1,000 mg/kg) which kill most cells in DNA synthesis. Two days later the marrow becomes enriched in pluripotent stem cells (CFU-S) and committed progenitors. It was found that fibroblastoid colony-forming-units (CFU-F) become concentrated approximately four fold above controls and give rise to significantly larger fibroblastoid colonies than CFU-F in control marrow. In split-phase semisolid agar cultures, i. e. adherent cells of HU-treated marrow (in under layers) and normal bone marrow cells (in upper layers), inhibition of G/M colonies in the upper layer in observed. In control split-phase cultures of both under layers and upper layers of normal bone marrow, CFU-C inhibition is by far less pronounced. In liquid cultures, pre-established adherent layers of HU-treated marrow have a stimulatory effect on normal marrow CFU-C. It is concluded that during increased demand for pluripotent stem cells and progenitors, such as after HU administration, marrow stromal cells and possibly other adherent cells produce inhibitory factor(s) of CFU-C differentiation. The inhibitory activity possibly is an effective mechanism for stem cell pool preservation. The differing effect of adherent cells of HU-treated marrow on CFU-C in liquid and in semi-solid medium suggests production of two different factors with opposing influences on CFU-C, depending upon the culture conditions.
Peripheral blood T cell colony forming cells (T-CFC) are mature T cells. When blood was fractionated into sheep red blood cell receptor positive (E+) and negative (E-) fractions, T cell colony growth was largely restricted to the E+ population. When bone marrow was similarly fractionated, many colonies grew from the E- cells but myeloid colonies also grew making interpretation of colony numbers difficult. We have, therefore, also assessed T cell proliferation during culture as an expansion index (EI) by determining the absolute number of T cells pre and post culture. This data shows that T cell expansion is on average nine times greater in the E- marrow fraction than in the E+ fraction. Studies are presented suggesting that this is because marrow E- cells contain appropriate accessory cells and that high numbers of T cells inhibit T cell growth. The cells giving rise to bone marrow T cell colonies thus appear to be contaminating mature T cells rather than pre-thymic progenitor cells. We have measured T cell expansion in culture as a sensitive assay of T cell contamination following procedures to remove T cells from bone marrow grafts for the prevention of graft versus host disease (GVHD).
Human bone marrow contains plastic-adherent hemopoietic progenitor cells whose plating efficiency is increased by brief (2 h) exposure to methylprednisolone (MP). When subsequently covered with methylcellulose medium, they form colonies of monoblastoid cells. Colony size, but not number, and mature cell production are increased by erythropoietin (epo) and granulocyte-macrophage colony-stimulating factor (GM-CSF). However, colonies do not grow under serum-free conditions. The resistance of plastic-adherent progenitors to treatment with 5-fluorouracil (5FU), their growth pattern, and their capacity to produce granulocytic and erythroid colonies on replating, suggest that they may be similar to the primitive, 5FU-resistant, plastic-adherent progenitor cells (HPP-CFC) in murine marrow.
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To develop a highly efficient means for generating methotrexate resistant (MTXr) hematopoietic cells in vivo, a recombinant retroviral genome was constructed that encodes a MTXr dihydrofolate reductase (DHFRr). Cell lines producing high titers of virus capable of transmitting the DHFR gene were generated and used to infect mammalian cells in vitro. Analysis of infected fibroblasts indicated that the DHFRr gene was transmitted intact and conferred a high level of MTXr upon cells. Based on these findings, DHFRr-containing virus was used to infect murine bone marrow cells in vitro. Following infection, the transduced cells were introduced into lethally irradiated recipients via bone marrow transplantation techniques. The presence of the proviral sequences in cells of the spleen and bone marrow of engrafted recipients was associated with significantly increased survival of mice treated with otherwise lethal doses of MTX.
Bone marrow suppression developed in a patient while she was on a regimen of sodium valproate. In addition, she had high titers of platelet autoantibodies and a coagulopathy, both recognized complications of valproate therapy. It is postulated that this drug was also responsible for the marrow suppression.
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Between 1979 and 1982, 192 patients with acute lymphoblastic leukaemia were given allogenic bone marrow transplants from HLA-identical siblings. Data on 57 patients transplanted in first remission were compared with the results in 96 patients transplanted in second remission, and 39 in third or subsequent remission. The majority of these patients were of the non-B non-T-ALL and T-ALL subtypes. The 2-year actuarial survival for non-B non-T-ALL was 58% for patients transplanted in first remission, 34% for second remission patients and 33% for patients transplanted in third or subsequent remission (P = 0.60). For patients with T-ALL, the survivals at 2 years for first and second remission transplant patients were 61% and 10%, respectively (P = 0.04). Multifactorial analysis demonstrated a significantly higher probability of survival for patients grafted in first remission (compared with more advanced remission states) and with bone marrow from young (age less than or equal to 20 years) donors. The 2-year actuarial risk of relapse for patients with non-B non-T-ALL transplanted in first remission was 0%, 32% and 69% for second and third or subsequent remission patients, respectively (P = 0.04). For T-ALL the actuarial risk of relapse at 2 years is 10% for first remission grafts and 48% for second remission grafts (P = 0.07). Only patients (with both non-B non-T/and T-ALL) transplanted in first remission have a high and stable probability of remaining in remission.