Replacement of recipient stromal/mesenchymal cells after bone marrow transplantation using bone fragments and cultured osteoblast-like cells

Cahill, Richard A.; Jones, Olcay Y.; Klemperer, Martin R.; Steele, Anne; Mueller, Thomas; El‐Badri, Nagwa; Chang, Yu-Ling; Good, Robert A.

doi:10.1016/j.bbmt.2004.06.001

Cited by 41 publications

(26 citation statements)

References 70 publications

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“…In our pilot study, we demonstrated that marrow osteoprogenitors can engraft in bone giving rise to donor-derived osteoblasts, modify the microscopic structure of the bone, and promote clinical benefits for children with OI, suggesting a contribution to osteogenesis [13,14]. Subsequent to our initial report, other investigators demonstrated that hypophosphatasia, another genetic disorder of bone, may also be treated with BMT [15,16], independently validating our original findings.…”

Section: Introductionsupporting

confidence: 62%

Transplantable marrow osteoprogenitors engraft in discrete saturable sites in the marrow microenvironment

Marino

Martinez

Boyd

et al. 2008

Experimental Hematology

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Objective-Based on the recognition that marrow contains progenitors for bone as well as blood, we undertook the first trial of bone marrow transplantation (BMT) for a genetic disorder of bone, osteogenesis imperfecta (OI). While we documented striking clinical benefit soon after transplantation, the measured level of osteopoietic engraftment was low. To improve the efficacy of BMT for bone disorders, we sought to gain insight into the cellular mechanism of engraftment of transplantable marrow osteoprogenitors.Methods-We transplanted unfractionated bone marrow harvested from green fluorescent protein (GFP)-transgenic FVB/N mice into lethally irradiated FVB/N recipients. At 3 weeks posttransplantation, we assessed hematopoietic engraftment by flow cytometry and osteopoietic engraftment by immunohistochemical staining for the GFP protein.Results-We show that the engraftment of transplantable marrow osteoprogenitors is saturable with a maximal engraftment of about 15% of all bone cells in the epiphysis and metaphysis of the femur at 3 weeks after transplantation. The number of engrafting sites is not up-or downregulated in response to initial progenitor cell engraftment and there is no evidence for clonal succession of osteopoietic differentiation of engrafted progenitors.Conclusions-Our findings indicate that the capacity for initial osteopoietic engraftment after BMT is limited and "megadose" stem cell transplantation is unlikely to enhance engraftment. Thus, novel strategies to foster osteopoietic chimerism must be developed.

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Section: Introductionsupporting

confidence: 62%

Transplantable marrow osteoprogenitors engraft in discrete saturable sites in the marrow microenvironment

Marino

Martinez

Boyd

et al. 2008

Experimental Hematology

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“…The procedure used a heterogeneous transplantation approach comprised of transplanting bone fragments placed intraperitoneally and directly into bone along with cultured osteoblastlike cells and fully matched marrow grafts. 96,97 The protocol included marrow infusion in which 2 biopsy cores obtained from the donors' iliac crests were inserted intraperitoneally and 2 were inserted directly into each recipient's iliac crest on day 0 of the transplantation procedure. Two bone fragments from each donor were used to culture osteoblastlike cells that were subsequently given by intravenous infusion on day ϩ13.…”

Section: What Is the Role Of Osteoblasts In Transplantation?mentioning

confidence: 99%

Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche

Taichman

2005

Blood

540

370

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The mechanisms of bone and blood formation have traditionally been viewed as distinct, unrelated processes, but compelling evidence suggests that they are intertwined. Based on observations that hematopoietic precursors reside close to endosteal surfaces, it was hypothesized that osteoblasts play a central role in hematopoiesis, and it has been shown that osteoblasts produce many factors essential for the survival, renewal, and maturation of hematopoietic stem cells (HSCs). Preceding these observations are studies demonstrating that the disruption or perturbation of normal osteoblastic function has a profound and central role in defining the operational structure of the HSC niche. These observations provide a glimpse of the dimensions and ramifications of HSC-osteoblast interactions. Although more research is required to secure a broader grasp of the molecular mechanisms that govern blood and bone biology, the central role for osteoblasts in hematopoietic stem cell regulation is reviewed herein from the perspectives of (1) historical context; (2) the role of the osteoblast in supporting stem cell survival, proliferation, and maintenance; (3) the participation, if any, of osteoblasts in the creation of a stem cell niche; (4) the molecules that mediate HSC-osteoblast interactions; (5) the role of osteoblasts in stem cell transplantation; and (6) Introduction and historical perspectiveHematopoiesis occurs in unique microenvironments that facilitate the maintenance of hematopoietic stem cells (HSCs) as pluripotent and support the maturation of progenitors. Each of these activities may require different growth factors and microenvironments, the identities of which have yet to be determined. In vitro, bone marrow stromal cells (BMSCs) serve as a rich source of growth factors for a variety of hematopoietic processes. BMSCs are composed of several different populations, including fibroblasts, macrophages, endothelial cells, and adipocytes. Although it is difficult to discern the relative importance of each of these cells, it has been shown that direct stromal cell-blood cell contact, BMSC production of the extracellular bone marrow matrix, and cytokine synthesis are all relevant to the formation and maturation of blood cells in vitro. [1][2][3] The role of BMSCs in vivo is less clear.Osteoblasts have long been known to play a central role in skeletal development. Derived from pluripotent mesenchymal stem cells (MSCs), they mature along a specific lineage to become highly specialized synthetic cells. As such, osteoblasts respond to many mechanical, local, and systemic stimuli that facilitate mineralization while they orchestrate bone remodeling. Osteoblasts also constitute part of the stromal cell support system in marrow, but little is known about their functional relevance to HSCs. Early attempts to understand this relationship focused on the protective function that bone might serve for the hematopoietic organ. 4 Observations in birds of recurrent trabeculation of the medullary cavity during ovulation show that the h...

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“…Her blood group converted from O to A (8 month post-transplant). On day +270, fibroblasts cultured from a bone biopsy specimen revealed 66% donor cells and a bone marrow specimen was 89% donor by short tandem repeat (STR) analysis [6], and now peripheral blood is >97%. Her pulmonary function tests for DLCO was 45% at 1 year, 63% at 3 years and 63% predicted at 6-year follow-ups.…”

Section: Nonmyeloablative Transplant Of Up5 and 6-year Follow-upmentioning

confidence: 99%

Nonmyeloablative allogeneic bone marrow transplantation of a child with systemic autoimmune disease and lung vasculitis

Jones

Cahill

2008

Immunol Res

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Replacement of recipient stromal/mesenchymal cells after bone marrow transplantation using bone fragments and cultured osteoblast-like cells

Cited by 41 publications

References 70 publications

Transplantable marrow osteoprogenitors engraft in discrete saturable sites in the marrow microenvironment

Transplantable marrow osteoprogenitors engraft in discrete saturable sites in the marrow microenvironment

Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche

Nonmyeloablative allogeneic bone marrow transplantation of a child with systemic autoimmune disease and lung vasculitis

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