Mesenchymal Stem Cells - Interest Group
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Despite the fact that MSCs can get trapped in the lungs, evidence has accumulated to show that
MSCs are capable of homing to injured tissues after IV delivery (
Table 1). Cultured rat and human
MSCs have been shown to migrate into sites of brain injury after cerebral ischemia when
transplanted intravenously in rats. Wu and colleagues delivered rat MSCs by the IV route to treat
heart allograft rejection in rats and found that they "vigorously migrated to sites of allograft
rejection," mainly differentiating into fibroblasts and a small number of myocytes. MSCs have also
been used to treat lung injury in mice when administered by the IV route. Ortiz and colleagues
found that murine MSCs home to lung in response to injury, adopt an epithelium-like phenotype,
and reduce inflammation and collagen deposition in the lung tissue of mice challenged with
bleomycin (a model of pulmonary fibrosis). They found a 23-fold increase in engraftment levels
of donor-derived cells when compared with mice not exposed to bleomycin.


Cultured MSCs have also been administered systemically to humans to treat several conditions,
including osteogenesis imperfecta (OI), a disease in which osteoblasts produce defective type I
collagen, which leads to osteopenia, multiple fractures, bone deformities, and shortened stature.
Horwitz and colleagues used bone marrow transplant (BMT) after ablative chemotherapy to treat
children with severe deforming OI. After 3 months, there was new dense bone formation, an
increase in total body bone mineral content, an increase in growth velocity, and reduced frequency
of bone fracture in all patients. This study demonstrates that mesenchymal progenitors in
transplanted marrow can migrate to bone in children with OI and then give rise to osteoblasts
whose presence correlates with an improvement in bone structure and function. However, with
increasing time post-transplantation, growth rate slowed and eventually reached a plateau, so it
was hypothesized that additional therapy using isolated hMSCs without marrow ablative therapy
would safely boost responses. They infused culture-expanded hMSCs into children who had
previously undergone conventional BMT and found that some cells engrafted in defective bone
and differentiated to osteoblasts capable of extending the clinical benefits of BMT. Thus,
allogeneic MSCs can be safely transplanted to children with OI without provoking an immune
response, and some cells home to the bone marrow.

Many studies have also investigated the use of MSCs for gene therapy, including transplantation
of MSCs transfected with vascular endothelial growth factor for the improvement of heart function
after MI in rats, MSCs as vehicles for interferon-β delivery into tumors in mice [66], and gene
therapy with MSCs expressing BMPs to promote bone formation . There is much evidence to
support the theory that MSCs can home to tissues, particularly when injured or inflamed, involving
migration across endothelial cell layers. The mechanism by which MSCs home to tissues and
migrate across endothelium is not yet fully understood, but it is likely that injured tissue
expresses specific receptors or ligands to facilitate trafficking, adhesion, and infiltration of MSCs
to the site of injury, as is the case with recruitment of leukocytes to sites of inflammation.
Chemokine receptors and their chemokine ligands are essential components involved in the
migration of leukocytes into sites of inflammation, and it has recently been shown that MSCs also
express some of these molecules. In addition, some of the adhesion molecules known to be
involved in migration of leukocytes across the endothelium are also reported to be expressed on
MSCs.


References:

  • Orlic D, Kajstura J, Chimenti S et al. Mobilized bone marrow cells repair the infarcted heart,
    improving function and survival. Proc Natl Acad Sci U S A 2001;98:10344–10349.

  • Jackson KA, Majka SM, Wang H et al. Regeneration of ischemic cardiac muscle and
    vascular endothelium by adult stem cells. J Clin Invest 2001;107:1395–1402.

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