Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass. Nat Med

Musculoskeletal Research Group, Department of Internal Medicine, University of California at Davis Medical Center, Sacramento, California, USA.
Nature medicine (Impact Factor: 27.36). 02/2012; 18(3):456-62. DOI: 10.1038/nm.2665
Source: PubMed


Aging reduces the number of mesenchymal stem cells (MSCs) that can differentiate into osteoblasts in the bone marrow, which leads to impairment of osteogenesis. However, if MSCs could be directed toward osteogenic differentiation, they could be a viable therapeutic option for bone regeneration. We have developed a method to direct MSCs to the bone surface by attaching a synthetic high-affinity and specific peptidomimetic ligand (LLP2A) against integrin α4β1 on the MSC surface to a bisphosphonate (alendronate, Ale) that has a high affinity for bone. LLP2A-Ale induced MSC migration and osteogenic differentiation in vitro. A single intravenous injection of LLP2A-Ale increased trabecular bone formation and bone mass in both xenotransplantation studies and in immunocompetent mice. Additionally, LLP2A-Ale prevented trabecular bone loss after peak bone acquisition was achieved or as a result of estrogen deficiency. These results provide proof of principle that LLP2A-Ale can direct MSCs to the bone to form new bone and increase bone strength.

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Available from: Jan A Nolta, Mar 24, 2015
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    • "These methods employ viral transduction to over-express CXCR4 [16], glycan engineering to enhance cellular sialyl Lewis-X (sLe x ) content [17], covalent coupling to conjugate sLe x [18] [19] or E-selectin binding peptides [20] on the cell surface, or non-covalent lipid based methods to couple antibodies against vascular adhesion molecules ICAM-1, VCAM-1 and MAdCAM-1 [21] [22]. In addition to ex vivo testing, some of these studies report success in enhancing MSC homing in vivo following systemic infusion [16] [17] [22] [23]. Despite these outcomes, strategies to further enhance the efficiency of MSC capture from flowing blood are necessary in order to reduce the number of MSCs applied during therapeutic interventions. "
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    ABSTRACT: Mesenchymal stem/stromal cells (MSCs) are an important candidate for cell-based therapy since they can be easily isolated and expanded, secrete beneficial paracrine factors, and differentiate into multiple lineages. Since the endothelium at sites of injury and inflammation often express adhesion molecules belonging to the selectin family, methods to endow MSCs with selectin-ligands can enhance the efficacy of cell delivery and tissue engraftment. Here, we describe a construct 19Fc[FUT7(+)], where the first 19 amino acids of the pan-selectin ligand PSGL-1 (P-selectin glycoprotein ligand-1) was fused to a human IgG1. When expressed in HEK293T cells over-expressing the α(1,3)fucosyltransferase FUT7, 19Fc[FUT7(+)] is decorated by a core-2 sialyl Lewis-X sialofucosylated O-glycan. The non-covalent coupling of this protein onto MSC surface using palmitated protein G (PPG) enhanced cell binding to E- and P-selectin under hydrodynamic shear, without altering MSC multipotency. MSCs functionalized with 19Fc[FUT7(+)] were captured/tethered onto stimulated endothelial cell monolayers at wall shear stresses up to 4 dyn/cm(2). Once captured, the cells rolled robustly up to the highest shear stress tested, 10 dyn/cm(2). Unlike previous work where MSCs could only be captured onto selectin-bearing substrates at low or no-flow conditions, the current work presents a 'glycan engineering' strategy to enable leukocyte-like capture and rolling.
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    • "hMSCs are characterized by the ability to maintain quiescent, replicate (self-renew) with high proliferative rates, and differentiate into different lineages (Tavassoli and Crosby, 1968; Pittenger et al., 1999). Different investigators highlighted the capacity of hMSCs to differentiate in various cellular phenotype including chondrocytes, osteoblasts, adipocytes, myocytes, and neurons (Zuk et al., 2002; Gang et al., 2004; Kern et al., 2006; Karahuseyinoglu et al., 2007; Guan et al., 2012). Different are also the tissues in which hMSCs are found and can be isolated (Fig. 1). "
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    ABSTRACT: The continuous discovery of human mesenchymal stem cells (hMSCs) in different tissues is stirring up a tremendous interest as a cell source for regenerative medicine therapies. Historically, hMSCs have been always considered a sub-population of mononuclear cells present in the bone marrow (BM). Although BM-hMSCs are still nowadays considered as the most promising mesenchymal stem cell population to reach the clinics due to their capacity to differentiate into multiple tissues, hMSCs derived from other adult and foetal tissues have also demonstrated to possess similar differentiation capacities. Furthermore, different reports have highlighted a higher recurrence of hMSCs in some of these tissues as compared to BM. This offer a fascinating panorama for cell banking, since the creation of a stem cell factory could be envisioned where hMSCs are stocked and used for ad hoc clinical applications. In this review, we summarize the main findings and state of the art in hMSCs isolation, characterization, and differentiation from alternative tissue sources and we attempt to compare their potency for musculoskeletal regeneration. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.
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    • "ZA is now undergoing clinical trials with various other adjuvant therapies[11]. Another interesting use of bisphosphonates was highlighted in a recent study that used alendronate, conjugated to a peptidomimetic ligand against activated integrin α4β1, to serve as a bone-seeking agent to direct the therapeutic compound to the bone[60]. "
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