Mobilization Of Bone Marrow-derived Stem Cells Research Articles

Endogenous Bone Marrow-Derived Stem Cell Mobilization and Homing for In Situ Tissue Regeneration.

In mammals, post-injury repair and regenerative events rely predominantly on stem cell function. Stem cell transplantation has achieved considerable success in animals but remains unfavorable for humans because of the unavoidable drawbacks. Nevertheless, substantial evidence suggests the regenerative potential of endogenous stem cells can be improved for functional and structural recovery of tissue damage or in disease conditions. Endogenous stem cells are mostly quiescent under steady-state conditions and reside in their niche. Once faced with tissue injury, physiological and molecular changes within the niche or from distant tissues activate the migration, proliferation, and differentiation of stem cells, contributing to tissue repair. Tissue regeneration is augmented by artificially amplifying the factors that promote stem cell mobilization or enhance the homing of endogenous stem cells. This cell-free strategy, known as "in situ tissue regeneration," represents a safer and more efficient means to conduct tissue regeneration. Bone marrow (BM) is considered the central niche and main reservoir of many types of stem cells. These stem cells hold great therapeutic potential for the regeneration of multiple injured tissues. Herein, we review recent strategies for promoting in situ tissue regeneration through BM-derived stem cell mobilization or homing in animal models as well as in human trials. With the advancement in biomaterial engineering, chemoattractant signals combined with functionalized bioscaffolds have accomplished sustained activation of endogenous BM-derived stem cells that can be used as an attractive strategy for efficient in situ tissue regeneration.

Evidence of Stem Cells Mobilization in the Blood of Patients with Pancreatitis: A Potential Link with Disease Severity.

A growing number of studies indicate the potential involvement of various populations of bone marrow-derived stem cells (BMSCs) in tissue repair. However, the mobilization of BMSCs to the peripheral blood (PB) in acute and chronic pancreatitis (AP and CP) has not been investigated. A total of 78 patients were assigned into AP, CP, and healthy control groups in this study. Using flow cytometry, we found that VSELs, EPCs, and CD133+SCs were mobilized to the PB of patients with both AP and CP. Interestingly, AP and CP patients exhibited lower absolute number of circulating MSCs in the PB compared to healthy individuals. SC mobilization to the PB was more evident in patients with AP than CP and in patients with moderate/severe AP than mild AP. Using ELISA, we found a significantly increased HGF concentration in the PB of patients with AP and SDF1α in the PB of patients with CP. We noted a significant positive correlation between SDF1α concentration and the mobilized population of CD133+SCs in AP and between C5a and the mobilized population of VSELs moderate/severe AP. Thus, bone marrow-derived SCs may play a role in the regeneration of pancreatic tissue in both AP and CP, and mobilization of VSELs to the PB depends on the severity of AP.

CXCR4 ANTAGONIST AMD3100 PROMOTES MILD IMPROVEMENTS OF CARDIAC FUNCTION AND PULMONARY MECHANICS IN PULMONARY HYPERTENSIVE RATS

Background Pulmonary arterial hypertension (PAH) is a lethal cardiopulmonary disease characterized by an increase in resting pulmonary pressure ≥25 mmHg. Poor survival and functional limitations of PAH patients have fueled research for new alternative therapeutic strategies. So far, pre-clinical findings suggested promising effects of stem cell-based therapies. AMD3100 is a highly selective CXCR4 antagonist that enhances autologous bone marrow-derived stem cell mobilization and is currently used in stem cell transplantation and the treatment of leukemia. So far, however, it remains unclear whether AMD3100 can provide salutary effects in the treatment of PAH. Methods PAH was induced in adult male Wistar rats (Protocol number 087/15) by an intraperitoneal injection of monocrotaline (MCT, 60 mg/kg IP), while the Control (CTL) group was treated an equivalent volume of vehicle. Two weeks after the MCT injection, MCT-administered rats were randomly treated with AMD3100 (1 mg/kg/day IP for 14 days) or vehicle, totalling 3 groups: CTL, MCT, and AMD3100. Echocardiography and pneumotachography were used to assess cardiac function and pulmonary mechanics, respectively. Right ventricular (RV) hypertrophy was assessed by the Fulton index. Data were analyzed with One-way and Two-way ANOVA (Prism®, GraphPad) and were expressed as mean ± SEM. Results MCT and AMD3100 groups exhibited an equally progressive decrease in body weight compared to the CTL group (p Conclusion Our study indicates that treatment with AMD3100 provides mild improvement of cardiac and pulmonary function in pulmonary hypertensive rats.

CXCL12/SDF-1-Dependent Retinal Migration of Endogenous Bone Marrow-Derived Stem Cells Improves Visual Function after Pharmacologically Induced Retinal Degeneration.

Mobilized bone marrow-derived stem cells (BMSC) have been discussed as an alternative strategy for endogenous repair. Thereby, different approaches for BMSC mobilization have been pursued. Herein, the role of a newly discovered oligonucleotide for retinal homing and regeneration capability of BMSCs was investigated in the sodium iodate (NaIO3) model of retinal degeneration. Mobilization was achieved in GFP-chimera with NOX-A12, a CXC-motif chemokine ligand 12 (CXCL12)/stromal cell-derived factor 1 (SDF-1)-neutralizing L-aptamer. BMSC homing was directed by intravitreal SDF-1 injection. Visual acuity was measured using the optokinetic reflex. Paraffin cross sections were stained with hematoxylin and eosin for retinal thickness measurements. Immunohistochemistry was performed to investigate the expression of cell-specific markers after mobilization. A single dose of NOX-A12 induced significant mobilization of GFP+ cells which were found in all layers within the degenerating retina. An additional intravitreal injection of SDF-1 increased migration towards the site of injury. Thereby, the number of BMSCs (Sca-1+) found in the damaged retina increased whereas a decrease of activated microglia (Iba-1+) was found. The mobilization led to significantly increased visual acuity. However, no significant changes in retinal thickness or differentiation towards retinal cell types were detected. Systemic mobilization by a single dose of NOX-A12 showed increased homing of BMSCs into the degenerated retina, which was associated with improved visual function when injection of SDF-1 was additionally performed. The redistribution of the cells to the site of injury combined with their observed beneficial effects support the endogenous therapeutic strategy for retinal repair.

Concise Review: Pancreatic Cancer and Bone Marrow-Derived Stem Cells.

Pancreatic adenocarcinoma remains one of the most challenging diseases of modern gastroenterology, and, even though considerable effort has been put into understanding its pathogenesis, the exact molecular mechanisms underlying the development and/or systemic progression of this malignancy still remain unclear. Recently, much attention has been paid to the potential role of bone marrow-derived stem cells (BMSCs) in this malignancy. Hence, herein, we comprehensively review the most recent discoveries and current achievements and concepts in this field. Specifically, we discuss the significance of identifying pancreatic cancer stem cells and novel therapeutic approaches involving molecular interference of their metabolism. We also describe advances in the current understanding of the biochemical and molecular mechanisms responsible for BMSC mobilization during pancreatic cancer development and systemic spread. Finally, we summarize experimental, translational, and/or clinical evidence regarding the contribution of bone marrow-derived mesenchymal stem cells, endothelial progenitor cells, hematopoietic stem/progenitor cells, and pancreatic stellate cells in pancreatic cancer development/progression. We also present their potential therapeutic value for the treatment of this deadly malignancy in humans. Different bone marrow-derived stem cell populations contribute to the development and/or progression of pancreatic cancer, and they might also be a promising "weapon" that can be used for anticancer treatments in humans. Even though the exact role of these stem cells in pancreatic cancer development and/or progression in humans still remains unclear, this concept continues to drive a completely novel scientific avenue in pancreatic cancer research and gives rise to innovative ideas regarding novel therapeutic modalities that can be safely offered to patients.

Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman's syndrome and endometrial atrophy: a pilot cohort study.

Could cell therapy using autologous peripheral blood CD133+ bone marrow-derived stem cells (BMDSCs) offer a safe and efficient therapeutic approach for patients with refractory Asherman's syndrome (AS) and/or endometrial atrophy (EA) and a wish to conceive? In the first 3 months, autologous cell therapy, using CD133+ BMDSCs in conjunction with hormonal replacement therapy, increased the volume and duration of menses as well as the thickness and angiogenesis processes of the endometrium while decreasing intrauterine adhesion scores. AS is characterized by the presence of intrauterine adhesions and EA prevents the endometrium from growing thicker than 5 mm, resulting in menstruation disorders and infertility. Many therapies have been attempted for these conditions, but none have proved effective. This was a prospective, experimental, non-controlled study. There were 18 patients aged 30-45 years with refractory AS or EA were recruited, and 16 of these completed the study. Medical history, physical examination, endometrial thickness, intrauterine adhesion score and neoangiogenesis were assessed before and 3 and 6 months after cell therapy. After the initial hysteroscopic diagnosis, BMDSC mobilization was performed by granulocyte-CSF injection, then CD133+ cells were isolated through peripheral blood aphaeresis to obtain a mean of 124.39 million cells (range 42-236), which were immediately delivered into the spiral arterioles by catheterization. Subsequently, endometrial treatment after stem cell therapy was assessed in terms of restoration of menses, endometrial thickness (by vaginal ultrasound), adhesion score (by hysteroscopy), neoangiogenesis and ongoing pregnancy rate. The study was conducted at Hospital Clínico Universitario of Valencia and IVI Valencia (Spain). All 11 AS patients exhibited an improved uterine cavity 2 months after stem cell therapy. Endometrial thickness increased from an average of 4.3 mm (range 2.7-5) to 6.7 mm (range 3.1-12) ( ITALIC! P = 0.004). Similarly, four of the five EA patients experienced an improved endometrial cavity, and endometrial thickness increased from 4.2 mm (range 2.7-5) to 5.7 mm (range 5-12) ( ITALIC! P = 0.03). The beneficial effects of the cell therapy increased the mature vessel density and the duration and intensity of menses in the first 3 months, with a return to the initial levels 6 months after the treatment. Three patients became pregnant spontaneously, resulting in one baby boy born, one ongoing pregnancy and a miscarriage. Furthermore, seven pregnancies were obtained after fourteen embryo transfers, resulting in three biochemical pregnancies, one miscarriage, one ectopic pregnancy, one baby born and one ongoing pregnancy. Limitations of this pilot study include the small sample size and the lack of control group. This novel autologous cell therapy is a promising therapeutic option for patients with these incurable pathologies and a wish to conceive. This study was funded by the Spanish Ministry of Science and Innovation (SAF 2012-31017, Principal Investigator C.S.), Spanish Ministry of Health (EC11-299, Principal Investigator C.S.) and Regional Valencian Ministry of Education (PROMETEOII/2013/018, Principal Investigator C.S.). Four authors (X.S., I.C., A.P. and C.S.) are co-inventors of the patent resulting from this work (Application number: 62/013,121). S.C., C.A., F.R., J.F., J.P. and J.R. have no conflict of interest in relation to this work. This study was registered with ClinicalTrials.gov (NCT02144987).

Overview of Bone Marrow-Derived Stem Cell Mobilization for Treating Cardiovascular and Cerebrovascular Diseases

Large numbers of patients worldwide suffer from cardiovascular and cerebrovascular diseases, including stroke, myocardial ischemia and critical limb ischemia. Therapeutic angiogenesis aims to induce, augment and control the host angiogenic response in order to revascularization in ischemic tissues, and often involves delivery of growth factors or stem/progenitor cells. Therapeutic angiogenesis for coronary or peripheral arterial diseases are directed to relieving symptoms of ischemia; preventing target organ damage due to hypoxia, reperfusion or capillary leak; and avoiding cardiovascular catastrophes due to acute thrombosis, embolism, plaque rupture or dissection. Bone marrow-derived stem cells (BMSCs) are adult stem cells with capacity for self-renewal and multi-lineage differentiation. Mobilization of BMSCs to ischemic tissue for regeneration and repair is emerging as an extremely promising therapeutic agent for cardiovascular and cerebrovascular disease. The purpose of this review is to summarize current status about drugs or cytokines for stem cell mobilization in treating cardiovascular and cerebrovascular diseases.

Effects of autologous bone marrow-derived stem cell mobilization on acute tubular necrosis and cell apoptosis in rats.

The aim of this study was to investigate the effects of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) on bone marrow-derived stem cell (BMSC) mobilization in rat models of renal ischemia/reperfusion (I/R) injury. In addition, the effects of SCF and G-CSF on cellular apoptosis were explored in order to determine the protective mechanism of the two factors against renal I/R injury. A unilateral renal I/R injury model was established for the model and treatment groups. The treatment and treatment control groups were subcutaneously injected with SCF (200 µg/kg/day) and G-CSF (50 µg/kg/day) 24 h after the establishment of the model for five consecutive days. The total number of leukocytes in the peripheral blood and the cellular percentages of cluster of differentiation (CD)34+, renal CD34+ and apoptotic cells were detected. The total number of leukocytes in the peripheral blood and the percentages of CD34+ cells in the treatment and treatment control groups reached maximum levels on the fifth postoperative day and were significantly higher than those in the normal control and model groups. The number of renal CD34+ cells in the treatment group was significantly increased compared with that in the treatment control and model groups. The apoptotic indices (AIs) of the model and treatment groups were higher than those of the normal control and treatment control groups. The AI of the model group was significantly higher than that of the treatment group. In conclusion, the combined application of SCF and G-CSF can mobilize sufficient numbers of BMSCs and cause cellular 'homing' to the injured site, thus inhibiting apoptosis and promoting the repair of renal tubular injury.

Attenuation of cardiac hypertrophy by G-CSF is associated with enhanced migration of bone marrow-derived cells.

Granulocyte-colony stimulating factor (G-CSF) has been shown to promote mobilization of bone marrow-derived stem cells (BMCs) into the bloodstream associated with improved survival and cardiac function after myocardial infarction. Therefore, the aim of the present study was to investigate whether G-CSF is able to attenuate cardiac remodelling in a mouse model of pressure-induced LV hypertrophy focusing on mobilization and migration of BMCs. LV hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6J mice. Four weeks after TAC procedure. Mice were treated with G-CSF (100 μg/kg/day; Amgen Biologicals) for 2 weeks. The number of migrated BMCs in the heart was analysed by flow cytometry. mRNA expression and protein level of different growth factors in the myocardium were investigated by RT-PCR and ELISA. Functional analyses assessed by echocardiography and immunohistochemical analysis were performed 8 weeks after TAC procedure. G-CSF-treated animals revealed enhanced homing of VLA-4+ and c-kit+ BMCs associated with increased mRNA expression and protein level of the corresponding homing factors Vascular cell adhesion protein 1 and Stem cell factor in the hypertrophic myocardium. Functionally, G-CSF significantly preserved LV function after TAC procedure, which was associated with a significantly reduced area of fibrosis compared to control animals. Furthermore, G-CSF-treated animals revealed a significant improvement of survival after TAC procedure. In summary, G-CSF treatment preserves cardiac function and is able to diminish cardiac fibrosis after induction of LV hypertrophy associated with increased homing of VLA-4+ and c-kit+ BMCs and enhanced expression of their respective homing factors VCAM-1 and SCF.

Safety and feasibility of intramyocardial versus intracoronary delivery of autologous cell therapy in advanced heart failure: the REGENERATE-IHD pilot study.

This study presents an interim safety and feasibility analysis of the REGENERATE-IHD randomized controlled trial, which is examining the safety and efficacy of three different delivery routes of bone marrow-derived stem cells (BMSCs) in patients with ischemic heart failure. The first 58 patients recruited to the REGENERATE-IHD study are included in this interim analysis (pilot). Symptomatic patients with ischemic heart failure were randomized to receive subcutaneous granulocyte colony-stimulating factor or saline injections only; or subcutaneous granulocyte colony-stimulating factor injections followed by intracoronary or intramyocardial injections of BMSCs or serum (control). No significant differences were found in terms of safety and feasibility between the different delivery routes, with no significant difference in procedural complications or major adverse cardiac events. There was a signal towards improved heart failure symptoms in the patients treated with intramyocardial injection of mobilized BMSCs. Peripheral mobilization of BMSCs with or without subsequent direct myocardial delivery appears safe and feasible in patients with chronic ischemic heart failure.

Impact of parathyroid hormone on bone marrow-derived stem cell mobilization and migration.

Parathyroid hormone (PTH) is well-known as the principal regulator of calcium homeostasis in the human body and controls bone metabolism via actions on the survival and activation of osteoblasts. The intermittent administration of PTH has been shown to stimulate bone production in mice and men and therefore PTH administration has been recently approved for the treatment of osteoporosis. Besides to its physiological role in bone remodelling PTH has been demonstrated to influence and expand the bone marrow stem cell niche where hematopoietic stem cells, capable of both self-renewal and differentiation, reside. Moreover, intermittent PTH treatment is capable to induce mobilization of progenitor cells from the bone marrow into the bloodstream. This novel function of PTH on modulating the activity of the stem cell niche in the bone marrow as well as on mobilization and regeneration of bone marrow-derived stem cells offers new therapeutic options in bone marrow and stem cell transplantation as well as in the field of ischemic disorders.

Perioperative release of pro-regenerative biochemical signals from human renal allografts subjected to ischemia–reperfusion injury

Complement-derived molecules modulate the intensity of renal ischemia-reperfusion injury and may lead to the generation of biochemical signals [such as stromal-derived factor-1 (SDF-1) or sphingosine-1-phosphate (S1P)], which stimulate tissue/organ regeneration after injury. We tested the association between perioperative C5b-9/membrane attack complex (MAC) levels and intensified erythrocyte lysis, and asked whether significant changes in the levels of pro-regenerative substances occur during the early phase of renal allograft reperfusion. Seventy-five recipients were enrolled and divided into the early, slow, and delayed graft function (DGF) groups. Perioperative blood samples were collected from the renal vein during consecutive minutes of reperfusion. Extracellular hemoglobin (eHb), albumin (plasma S1P transporter), 8-iPF2α-III isoprostane, SDF-1 and S1P concentrations were measured. Throughout the reperfusion period, erythrocyte lysis intensified and was most pronounced in the DGF group. However, perioperative eHb levels did not correlate significantly with C5b-9/MAC values, but rather with the intensity of oxidative stress. No significant changes were observed in S1P, its plasma transporter (albumin) or SDF-1 levels, which were relatively low in all groups throughout the reperfusion period. Our study therefore demonstrates that no known biochemical signal for bone marrow-derived stem cell mobilization is released from human renal allografts to the periphery during the early phase of reperfusion.

Circulating bone marrow-derived stem cells in patients with pancreatic cancer.

200 Background: Various experimental studies suggest that bone marrow-derived stem cells (BMSCs) may be involved in the development and progression of pancreatic cancer. However, these observations require further studies, and delineation of exact mechanisms responsible for mobilization of BMSCs from the bone marrow to peripheral blood. Methods: A total of 23 patients with newly diagnosed pancreatic cancer (17 with distal metastases) and 15 healthy individuals were recruited to this study. Using fluorescence-activated cell sorter circulating hematopoietic (HSPCs), mesenchymal (MSCs), endothelial (EPCs), and very small embryonic/epiblast-like stem cells (VSELs) were enumerated and sorted. Plasma levels of various growth/inhibitory factors (hepatocyte [HGF], vascular-endothelial [VEGF], leukemia [LIF]), stem cells’ chemoattractants (stromal-derived factor-1 [SDF-1], sphingosine-1-phosphate [S1P]), and complement molecules (anaphylatoxins [C3a, C5a] and complexes [C5b-9/MAC]) were measured. Results: Significantly higher numbers of circulating VSELs and MSCs were detected in pancreatic cancer patients (in both p<0.05), while the numbers of circulating HSPCs and EPCs were comparable between the analyzed groups. Among analyzed biochemical and immunomodulatory factors, levels of C5a, C5b-9/MAC, HGF and S1P, but not of SDF-1, LIF nor VEGF were associated with observed mobilization of BMSCs. Conclusions: In patients with pancreatic cancer selective mobilization of BMSCs from the bone marrow to peripheral blood is observed. This seems to be strongly associated with increased levels of immunomodulatory substances. Our study also highlights that it is S1P and HGF but not SDF-1 that seem to be associated with BMSCs mobilization from the bone marrow to peripheral blood in patients with pancreatic cancer. (MNiSW grant 402 423038).

Stromal cell-derived factor-1 alpha (SDF-1α) improves neural recovery after spinal cord contusion in rats

Stromal cell-derived factor-1 alpha (SDF-1α) is an important cytokine, implicated in the control of stem cell trafficking and bone marrow-derived stem cell mobilization. Generally, SDF-1α regulates multiple physiological processes such as embryonic development and organ homeostasis. There is also good evidence that SDF-1α and its receptor CXCR411C-X-C chemokine receptor type 4. are key regulators of neurorepair processes after brain ischemia and spinal cord injury. In this study, we investigated the influence of chronic intrathecal delivery of SDF-1α after spinal cord contusion. After contusion T9, male Wistar rats at the age of 12 weeks were intrathecally treated with SDF-1α in different doses (100, 500 and 1000ng/ml) via an osmotic pump for 28 days. Thereafter, animals were subjected to an open field locomotor test. Behavioral scores were significantly higher in SDF-1α treated animals compared to placebo-treated groups. In addition, we evaluated histopathological changes in the spinal cord in the presence or absence of SDF-1α. Chronic delivery of SDF-1α decreased numbers of apoptotic cells, boosted astroglia and microglia response, induced angiogenesis, and potentiated the number of proliferating cells in a dose-dependent manner. These results clearly indicate an improved functional CNS long-term recovery after spinal cord injury. This behavioral restoration was paralleled by a reduction of apoptosis and changes in neuroinflammatory cells.

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

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.

Erythropoietin administration after myocardial infarction in mice attenuates ischemic cardiomyopathy associated with enhanced homing of bone marrow‐derived progenitor cells via the CXCR‐4/SDF‐1 axis

Mobilization of bone marrow-derived stem cells (BMCs) was shown to have protective effects after myocardial infarction (MI). However, the classical mobilizing agent, granulocyte-colony stimulating factor (G-CSF) relapsed after revealing an impaired homing capacity. In the search for superior cytokines, erythropoietin (EPO) appears to be a promising agent. Therefore, we analyzed in a murine model of surgically induced MI the influence of EPO treatment on survival and functional parameters as well as BMC mobilization, homing, and effect on resident cardiac stem cells (CSCs). Human EPO was injected intraperitoneally after ligation of the left anterior descendens (LAD) for 3 days with a total dose of 5000 IU/kg 6 and 30 days after MI, and pressure volume relationships were investigated in vivo. Cardiac tissues were analyzed by histology. To show the effect on BMCs and CSCs, FACS analyses were performed. Homing factors were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and ELISA. EPO-treated animals showed a significant improvement of survival post-MI (62 vs. 36%). At days 6 and 30, all hemodynamic parameters associated with attenuated remodeling, enhanced neovascularization, and diminished apoptotic cells in the peri-infarct area were improved. BMC subpopulations (CD31(+), c-kit(+), and Sca-1(+) cells) were mobilized, and homing of Sca-1(+) and CXCR4(+) BMCs toward an SDF-1 gradient into the ischemic myocardium was enhanced. However, there was no beneficial effect on CSCs. We have shown that EPO application after MI shows cardioprotective effects. This may be explained by mobilization of BMCs, which are homing via the CXCR-4/SDF-1 axis. However, EPO has no beneficial effects on resident CSCs. Therefore, new treatment regimes using EPO together with other agents may combine complementary beneficial effects preventing ischemic cardiomyopathy.

Stem cell mobilization versus stem cell homing: potential role for parathyroid hormone?

Stem cells are considered as potential candidates to regenerate the injured myocardium. It has been shown that stem cells are able to differentiate into cardiomyocytes, as recently reviewed.2 It is still an open question, however, whether such myocytes contribute to the functional recovery of the post-infarcted heart. This process is limited by the small number of cells that differentiate into cardiomyocytes, the limited coupling of pre-existing cardiomyocytes to these newly formed myocytes, and the question whether the overall increases in ejection fractions indeed depend on the amount of cardiomyocytes newly formed by stem cells. A specific pattern of matrix proteins may be expressed by these cells, they may mediate anti-apoptotic effects, or they may improve vascularization independent of a possible differentiation into cardiomyocytes. Such effects may be modified by stem cells acting in a paracrine manner. Irrespective of these open questions, research is ongoing to develop treatment protocols that increase the number of systemic stem cells that home to the injured myocardium.3,4 Zaruba et al. 1 used a novel and innovative approach to improve the homing of bone marrow-derived stem cells, as described in their article in the current issue of Cardiovascular Research . They tried to improve bone marrow-derived stem cell mobilization by application of parathyroid hormone (PTH), which affects … *Corresponding author. Tel. +49 641 99 47222; fax +49 641 99 47239. E-mail address : klaus-dieter.schlueter{at}physiologie.med.uni-giessen.de

Chronic Monotherapy With Rosuvastatin Prevents Progressive Left Ventricular Dysfunction and Remodeling in Dogs With Heart Failure

This study examined the effects of long-term monotherapy with rosuvastatin (RSV) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with heart failure (HF). 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or "statins" possess other noncholesterol-lowering properties that include inhibiting proinflammatory cytokines, attenuating LV hypertrophy, and stimulating the release of bone marrow-derived stem cells (BMSCs). Twenty-one dogs with microembolization-induced HF were randomized to 3 months oral monotherapy with low-dose (LD) RSV (0.5 mg/kg once daily, n = 7), high-dose (HD) RSV (3.0 mg/kg once daily, n = 7), or to no therapy (control group, n = 7). The change (Delta) from pre- to post-therapy (treatment effect) in LV end-diastolic volume (EDV) and end-systolic volume (ESV) and ejection fraction (EF) was measured. Protein level of tumor necrosis factor (TNF)-alpha in LV tissue and the number of circulating Sca-1-positive BMSCs was also determined. Blood and LV tissue from 6 normal dogs was obtained and used for comparison. There were no differences in DeltaEDV, DeltaESV, and DeltaEF between control group and LD RSV. In contrast, DeltaEDV and DeltaESV were significantly lower, and DeltaEF was significantly higher in HD RSV compared with control group. High-dose, but not LD, RSV also normalized protein levels of TNF-alpha and was associated with a significant increase in the number of circulating BMSCs. In dogs with HF, chronic therapy with HD RSV prevents progressive LV dysfunction and dilation. This benefit may be partly derived from normalization of TNF-alpha expression and partly from increased mobilization of BMSCs.

Homing genes, cell therapy and stroke

Stem cell therapies, such as bone marrow transplantation, are a promising strategy for the treatment of stroke. Bone marrow-derived stem cells (BMSCs) including both hematopoietic and mesenchymal stem cells (HSCs and MSCs) can exhibit tremendous cellular differentiation in numerous organs. BMSCs may also promote structural and functional repair in several organs such as the heart, liver, brain, and skeletal muscle via stem cell plasticity. Interestingly, ischemia is known to induce mobilization of BMSCs in both animal models and humans. The tissue injury is "sensed" by the stem cells and they migrate to the site of damage and undergo differentiation. The plasticity, differentiation, and migratory functions of BMSCs in a given tissue are dependent on the specific signals present in the local micro-environment of the damaged tissue. Therefore, the ischemic micro-environment has critical patho-biological functions that are essential for the seeding, expansion, survival, renewal, growth and differentiation of BMSCs in damaged brain remodeling. Recent studies have identified the specific molecular signals, such as SDF-1/CXCR4, required for the interaction of BMSCs and damaged host tissues. Understanding the exact molecular basis of stem cell plasticity in relation to local ischemic signals could offer new insights to permit better management of stroke and other ischemic disorders. The aim of this review is to summarize recent studies into how BMSCs reach, recognize, and function in cerebral ischemic tissues, with particular regard to phenotypical reprogramming of stem cells, or "stem cell plasticity".

Mobilization of bone marrow-derived stem cells after myocardial infarction and left ventricular function: simply effects of optimized drug treatment?

We thank Drs Thum and Bauersachs for their interest in our article.1 They correctly note that although we found transient mobilization of bone marrow-derived stem cells (BMSCs) after acute myocardial infarction (AMI) in man, Nygren et al. 2 failed to find mobilization of BMSCs after AMI in mice. Interestingly, two previous studies in the ‘human’ model have confirmed our observation of a transient increase in CD34+ cell count following AMI.3,4 This discrepancy …