Human Placenta-Derived Adherent Cells Prevent Bone loss, Stimulate Bone formation, and Suppress Growth of Multiple Myeloma in Bone

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Stem Cells (Impact Factor: 6.52). 02/2011; 29(2):263-73. DOI: 10.1002/stem.572
Source: PubMed


Human placenta has emerged as a valuable source of transplantable cells of mesenchymal and hematopoietic origin for multiple cytotherapeutic purposes, including enhanced engraftment of hematopoietic stem cells, modulation of inflammation, bone repair, and cancer. Placenta-derived adherent cells (PDACs) are mesenchymal-like stem cells isolated from postpartum human placenta. Multiple myeloma is closely associated with induction of bone disease and large lytic lesions, which are often not repaired and are usually the sites of relapses. We evaluated the antimyeloma therapeutic potential, in vivo survival, and trafficking of PDACs in the severe combined immunodeficiency (SCID)-rab model of medullary myeloma-associated bone loss. Intrabone injection of PDACs into nonmyelomatous and myelomatous implanted bone in SCID-rab mice promoted bone formation by stimulating endogenous osteoblastogenesis, and most PDACs disappeared from bone within 4 weeks. PDACs inhibitory effects on myeloma bone disease and tumor growth were dose-dependent and comparable with those of fetal human mesenchymal stem cells (MSCs). Intrabone, but not subcutaneous, engraftment of PDACs inhibited bone disease and tumor growth in SCID-rab mice. Intratumor injection of PDACs had no effect on subcutaneous growth of myeloma cells. A small number of intravenously injected PDACs trafficked into myelomatous bone. Myeloma cell growth rate in vitro was lower in coculture with PDACs than with MSCs from human fetal bone or myeloma patients. PDACs also promoted apoptosis in osteoclast precursors and inhibited their differentiation. This study suggests that altering the bone marrow microenvironment with PDAC cytotherapy attenuates growth of myeloma and that PDAC cytotherapy is a promising therapeutic approach for myeloma osteolysis.

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    • "Therefore, the novel therapeutic strategies are critically required to improve the clinical outcome of osteoporotic treatment. Multipotent mesenchymal stromal cells (MSCs), which have a capacity to differentiate to osteoblasts are considered to be the potential source for treating several bone diseases by cell replacement therapy [9] [10]. MSCs have been successfully isolated from various human tissues including bone marrow, adipose tissues, and postnatal tissues such as placenta [11] [12] [13]. "
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    ABSTRACT: Bortezomib (BZB) is a chemotherapeutic agent approved for treating multiple myeloma (MM) patients. In addition, there are several reports showing that bortezomib can induce murine mesenchymal stem cells (MSCs) to undergo osteogenic differentiation and increase bone formation in vivo. MSCs are the multipotent stem cells that have capacity to differentiate into several mesodermal derivatives including osteoblasts. Nowadays, MSCs mostly bone marrow derived have been considered as a valuable source of cell for tissue replacement therapy. In this study, the effect of bortezomib on the osteogenic differentiation of human MSCs derived from both bone marrow (BM-MSCs) and postnatal sources such as placenta (PL-MSCs) were investigated. The degree of osteogenic differentiation of BM-MSCs and PL-MSCs after bortezomib treatment was assessed by alkaline phosphatase (ALP) activity, matrix mineralization by Alizarin Red S staining and the expression profiles of osteogenic differentiation marker genes, Osterix, RUNX2 and BSP. The results showed that 1nM and 2nM BZB can induce osteogenic differentiation of BM-MSCs and PL-MSCs as demonstrated by increased ALP activity, increased matrix mineralization and up-regulation of osteogenic differentiation marker genes, Osterix, RUNX2 and BSP as compared to controls. The enhancement of osteogenic differentiation of MSCs by bortezomib may lead to the potential therapeutic applications in human diseases especially patients with osteopenia.
    Biochemical and Biophysical Research Communications 04/2014; 447(4). DOI:10.1016/j.bbrc.2014.04.044 · 2.30 Impact Factor
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    • "For example, hepatocyte growth factor (HGF) is expressed by some MSC cultures [7]. Standal et al. [8] reported that HGF decreased bone morphogenetic protein (BMP)-induced osteoblast activity and, hence, increased bone loss, in multiple myeloma (MM) bones, and Xu et al. [9] reported that bone marrow-derived MSCs (BM-MSCs) promoted MM cell growth, protected MM cells from drug-induced apoptosis, and shortened the life span of MM-bearing mice, while Li et al. [10] demonstrated that placenta-derived MSC-like cells prevented bone loss, stimulated bone formation and suppressed growth of MM in mouse bone. Similar inconsistencies of the therapeutic effects of MSCs from different origins or different preparations on tumor growth have been well documented [11]. "
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    ABSTRACT: Therapeutic potentials of mesenchymal stem cells (MSCs) from different sources have been evaluated in pre-clinical and clinical settings. Although MSCs from different sources share MSC-specific characteristics and functions, inconsistent or controversial results of pre-clinical and clinical applications of such cells are frequently reported. This may be partially due to the fact that MSCs isolated from different origins may differentially express some functions not typical for MSCs, and hence have different therapeutic potentials. The aim of this study is to investigate the differences in human placental MSCs (P-MSCs) of fetal and maternal origins in the aspects of clinical importance. P-MSCs of fetal and maternal origins isolated from normal term placentas were characterized for their typical phenotype as well as their expression of receptors and growth factors of clinic interests. P-MSCs that preferentially express hepatocyte growth factor (HGF) and CD200 were evaluated for their therapeutic potentials in models of angiogenesis and allogeneic skin transplantation, in comparison with their HGF and CD200 negative partners. Although all P-MSCs express typical MSC phenotype, fetal but not maternal P-MSCs express high levels of CD200 and HGF. Comparing with HGF and CD200 negative P-MSCs, HGF and CD200 positive cells demonstrated significantly high potentials in promoting angiogenesis in vitro and increasing immunosuppressive function in vivo. These therapeutic potentials were at least in part due to their differences in HGF and CD200 expression, respectively. We conclude that MSC origins may have significant impact on the therapeutic potentials of such cells, and should be taken into consideration in clinical applications.
    Stem Cell Research & Therapy 04/2014; 5(2):48. DOI:10.1186/scrt436 · 3.37 Impact Factor
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    • "Recent studies have revealed that exogenously injected MSCs were not detectable in vivo for long periods of time; the majority of these cells disappeared within 3 to 5 weeks [15,55]. Clinically, this phenomenon might be advantageous because it limits the duration of the intervention, and these observations support the notion that most of their activities are mediated through the touch-and-go mechanisms of bystander cells, although proof of such evanescence is thus far not well defined [5,56]. "
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    ABSTRACT: Cell-based therapy represents a new frontier in the treatment of a wide variety of human diseases traditionally associated with morbidity outcomes, including those involving inflammation, autoimmunity, tissue damage, and cancer. However, the use of mesenchymal stem cells (MSCs) to treat multiple myeloma (MM) bone disease has raised concerns. Specifically, evidence has shown that infused MSCs might support tumor growth and metastasis. In this study, we used a standard disseminated MM model in mice to identify the in vivo effects of intravenous MSC infusion. In addition, a series of in vitro co-culture assays were preformed to explore whether Fas/Fas-L is involved in the inhibitory effects of MSCs on MM cells. In the MM mouse model, treatment of MSCs with highly expressed Fas ligand (FasLhigh MSCs) showed remarkable inhibitory effects on MM indenization in terms of extending the mouse survival rate and inhibiting tumor growth, bone resorption in the lumbus and collum femoris, and MM cell metastasis in the lungs and kidneys. In addition, reduced proliferation and increased apoptosis of MM cells was observed when co-cultured with FasLhigh MSCs in vitro. Furthermore, mechanistically, the binding between Fas and Fas Ligand (Fas-L) significantly induced apoptosis in MM cells, as evidenced through an increase in the expression of apoptosis marker and Fas in MM cells. In contrast, FasLnull MSCs promote MM growth. These data suggest that Fas-L/Fas-induced MM apoptosis plays a crucial role in the MSC-based inhibition of MM growth. Although whether MSCs inhibit or promote cancer growth remains controversial, the levels of FasL expression in MSCs determine, at least partially, the effects of MSCs on MM cell growth.
    Stem Cell Research & Therapy 09/2013; 4(5):111. DOI:10.1186/scrt322 · 3.37 Impact Factor
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