Comparison of parathyroid hormone and G-CSF treatment after myocardial infarction on perfusion and stem cell homing

Abstract

Mobilization of stem cells by granulocyte colony-stimulating factor (G-CSF) was shown to have protective effects after myocardial infarction (MI); however, clinical trials failed to be effective. In search for alternative cytokines, parathyroid hormone (PTH) was recently shown to promote cardiac repair by enhanced neovascularization and cell survival. To compare the impact of the two cytokines G-CSF and PTH on myocardial perfusion, mice were noninvasively and repetitively investigated by pinhole single-photon emission computed tomography (SPECT) after MI. Mobilization and homing of bone marrow-derived stem cells (BMCs) was analyzed by fluorescence-activated cell sorter (FACS) analysis. Mice (C57BL/6J) were infarcted by left anterior descending artery ligation. PTH (80 mug/kg) and G-CSF (100 mug/kg) were injected for 5 days. Perfusion defects were determined by (99m)Tc-sestamibi SPECT at days 6 and 30 after MI. The number of BMCs characterized by Lin(-)/Sca-1(+)/c-kit(+) cells in peripheral blood and heart was analyzed by FACS. Both G-CSF and PTH treatment resulted in an augmented mobilization of BMCs in the peripheral blood. Contrary to G-CSF and controls, PTH and the combination showed significant migration of BMCs in ischemic myocardium associated with a significant reduction of perfusion defects from day 6 to day 30. A combination of both cytokines had no additional effects on migration and perfusion. In our preclinical model, SPECT analyses revealed the functional potential of PTH reducing size of infarction together with an enhanced homing of BMCs to the myocardium in contrast to G-CSF. A combination of both cytokines did not improve the functional outcome, suggesting clinical applications of PTH in ischemic heart diseases.

Parathyroid hormone 1-34 and skeletal anabolic action

“…The clinical significance of the SDF-1/CXCR4 axis has further been alluded to, whereby the overexpression of CXCR4 on mesenchymal stem cells leads to significant increases in bone mineral density, thus having implications in the treatment of osteoporosis. 78 In addition to a body of work from haematology and cardiologists, 79-81 Kitaori et al 82 demonstrated increased osteoblast expression of SDF-1 following intermittent PTH administration and thus upregulation of the stem cell homing axis SDF-1/CXCR4, with significant implications for endochondral repair and increased bone volume fraction. 82 …”

Endogenous Cell Therapy Improves Bone Healing

“…Although rhPTH has long been known to improve osteoblastic bone-forming parameters, there is some evidence to suggest that it may also act to enhance stem cell trafficking to sites of injury. [10][11][12]30,31 For example, Zaruba et al 12 and Huber et al 10 showed that systemic Teraparatide administration enhanced the homing of BM cells to the ischemic myocardium and reduced infarction size in mice. The authors postulated that the Teraparatide was acting by increasing the numbers of CD45 + /CD34 + cells trafficking to the myocardium, which resulted in increased vascular endothelial growth factor messenger RNA expression, increased neovascularization, and increased myocardial survival.…”

“…9 In efforts to improve bone healing and translate our results from animals to humans, herein, we investigate the effects of combining a vasculogenic PC-mobilizing agent with a PC-sensitizing agent to increase the effective trafficking of cPCs to the site of injury. [10][11][12] Because vasculogenesis is essential for osteogenesis, we hypothesized that critical-sized calvarial defects can be healed by increasing the number of cPCs with a stem-cell mobilizer, AMD3100, and improving cPC trafficking with a sensitizing agent, Teraparatide, recombinant human parathyroid hormone (rhPTH) (1-34).…”

Granulocyte Colony Stimulating Factor in the Treatment of Cardiac Ischemic Disease. A Decade has Passed: Is it Time to Give Up?

“…This was the first study within the first 6 years of the previous decade. In the last 4 years G-CSF has been associated to hepatocyte-growth factor [36], Flt-3 ligand [37], Fas, an antiapoptotic agent [38], parathyroid hormone [39] and erythropoietin [40][41][42][43] in animal models and even in humans [44] Electrophysiological properties…”