Background-Understanding the mechanisms of repair and regeneration of the kidney after injury is of great interest because there are currently no therapies that promote repair, and kidneys frequently do not repair adequately. We studied the capacity of human CD34 ϩ hematopoietic stem/progenitor cells (HSPCs) to promote kidney repair and regeneration using an established ischemia/reperfusion injury model in mice, with particular focus on the microvasculature. Methods and Results-Human HSPCs administered systemically 24 hours after kidney injury were selectively recruited to injured kidneys of immunodeficient mice (Jackson Labs, Bar Harbor, Me) and localized prominently in and around vasculature. This recruitment was associated with enhanced repair of the kidney microvasculature, tubule epithelial cells, enhanced functional recovery, and increased survival. HSPCs recruited to kidney expressed markers consistent with circulating endothelial progenitors and synthesized high levels of proangiogenic cytokines, which promoted proliferation of both endothelial and epithelial cells. Although purified HSPCs acquired endothelial progenitor markers once recruited to the kidney, engraftment of human endothelial cells in the mouse capillary walls was an extremely rare event, indicating that human stem cell mediated renal repair is by paracrine mechanisms rather than replacement of vasculature. Conclusions-These studies advance human HSPCs as a promising therapeutic strategy for promoting renal repair after injury. (Circulation. 2010;121:2211-2220.)
What determines the shape, size, and force output of cardiac and skeletal muscle? Chicago architect Louis Sullivan (1856-1924), father of the skyscraper, observed that "form follows function." This is as true for the structural elements of a striated muscle cell as it is for the architectural features of a building. Function is a critical evolutionary determinant, not form. To survive, the animal has evolved muscles with the capacity for dynamic responses to altered functional demand. For example, work against an increased load leads to increased mass and cross-sectional area (hypertrophy), which is directly proportional to an increased potential for force production. Thus a cell has the capacity to alter its shape as well as its volume in response to a need for altered force production. Muscle function relies primarily on an organized assembly of contractile and other sarcomeric proteins. From analysis of homogenized cells and molecular and biochemical assays, we have learned about transcription, translation, and posttranslational processes that underlie protein synthesis but still have done little in addressing the important questions of shape or regional cell growth. Skeletal muscles only grow in length as the bones grow; therefore, most studies of adult hypertrophy really only involve increased cross-sectional area. The heart chamber, however, can extend in both longitudinal and transverse directions, and cardiac cells can grow in length and width. We know little about the regulation of these directional processes that appear as a cell gets larger with hypertrophy or smaller with atrophy. This review gives a brief overview of the regulation of cell shape and the composition and aggregation of contractile proteins into filaments, the sarcomere, and myofibrils. We examine how mechanical activity regulates the turnover and exchange of contraction proteins. Finally, we suggest what kinds of experiments are needed to answer these fundamental questions about the regulation of muscle cell shape.
Compliance mismatch, thrombosis, and long culture times in vitro remain important challenges to the clinical implementation of a tissue-engineered small-diameter blood vessel (SDBV). To address these issues, we are developing an implantable elastomeric and biodegradable biphasic tubular scaffold. The scaffold design uses connected nonporous and porous phases as a basis to mimic, respectively, the intimal and medial layers of a blood vessel. Biphasic scaffolds were fabricated from poly(diol citrate), a novel class of biodegradable polyester elastomer. Scaffolds were characterized for tensile and compressive properties, burst pressure, compliance, foreign body reaction (via subcutaneous implantation in rats), and cell distribution and differentiation (via histology, scanning electron microscopy, and immunohistochemistry). Tensile tests, burst pressure, and compliance measurements confirm that the incorporation of a nonporous phase to create a "skin" connected to the porous phase of a scaffold can provide bulk mechanical properties that are similar to those of a native vessel. Compression tests confirm that the scaffolds are soft and recover from deformation. Subcutaneously implanted poly(diol citrate) porous scaffolds produce a thin fibrous capsule and allow for tissue ingrowth. In vitro culture of tubular biphasic scaffolds seeded with human aortic smooth muscle cells (HASMCs) and endothelial cells (HAECs) demonstrates the ability of this design to support cell compartmentalization, coculture, and cell differentiation. The newly formed HAEC monolayer stained positive for von Willebrand factor whereas collagen- and calponin-positive HASMCs were present in the porous phase.
To understand the role of tissue adaptation to altered physiological states, a more physiologically and dimensionally relevant in vitro model of cardiac myocyte organization has been developed. A microtextured polymeric membrane with micron range dimensions promotes myocyte adhesion through substrate/cell interlocking and, thus, provides a more suitable stretchable matrix for studying overlying cell populations. These microtextured membranes are created using photolithography and microfabrication techniques. Biologically, mechanically, and optically compatible interfaces with specified microarchitecture and surface chemistry have been designed, microfabricated, and characterized for this purpose. Cardiac myocytes plated on these membranes display greater attachment and cell height compared to conventional culture substrates. Advantages of the microtextured membranes include the high degree of reproducibility and the ability to create features on the micron and submicron size scale. Because of the flexibility of substrate material and the ease of creating micron size structures, this technique can be applied to many other physiological and biological systems.
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