Mobilization Of Endogenous Stem Cells Research Articles

Induction of Skin Allograft Chimerism by Pharmacological Mobilization of Endogenous Bone Marrow-Derived Stem Cells.

Skin substitutes including allografts remain a standard therapeutic approach to promote healing of both acute and chronic large wounds. However, none have resulted in the regrowth of lost and damaged tissues and scarless wound healing. Here, we demonstrate skin allograft chimerism and repair through the mobilization of endogenous bone marrow-derived stem and immune cells in rats and swine. We show that pharmacological mobilization of bone marrow stem cells and immune cells into the circulation promotes host repopulation of skin allografts and restoration of the skin's normal architecture without scarring and minimal contracture. When skin allografts from DA rats are transplanted into GFP transgenic Lewis recipients with a combination of AMD3100 and low-dose FK506 (AF) therapy, host-derived GFP-positive cells repopulate and/or regenerate cellular components of skin grafts including epidermis and hair follicles and the grafts become donor-host chimeric skin. Using AF combination therapy, burn wounds with skin allografts were healed by newly regenerated chimeric skin with epidermal appendages and pigmentation and without contracture in swine.

A phase I, first-in-human study to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of MRG-001 in healthy subjects

Preclinical studies demonstrate that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a fixed-dose drug combination (MRG-001) improves wound healing, promotes tissue regeneration, and prevents allograft rejection. In this phase I, first-in-human study, three cohorts receive subcutaneous MRG-001 or placebo, every other day for 5days. The primary outcome is safety and tolerability of MRG-001. Fourteen subjects received MRG-001 and seven received a placebo. MRG-001 is safe over the selected dose range. There are no clinically significant laboratory changes. The intermediate dose group demonstrates the most significant white blood cell, stem cell, and immunoregulatory cell mobilization. PBMC RNA sequencing and gene set enrichment analysis reveal 31 down-regulated pathways in the intermediate MRG-001 dose group compared with no changes in the placebo group. MRG-001 is safe across all dose ranges. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration (ClinicalTrials.gov: NCT04646603).

Electroacupuncture improves cardiac function after myocardial infarction by regulating the mobilization and migration of endogenous stem cells.

The aim of this study was to explore the role and mechanisms of electroacupuncture (EA) in the regulation of chemokines in endogenous stem cell mobilization and myocardial regeneration after myocardial infarction (MI). An MI model was constructed in adult male Sprague-Dawley rats by ligating the left anterior descending coronary artery. After 4 weeks of treatment, echocardiography was used to detect changes in cardiac function, and Masson's trichrome staining was used to detect collagen deposition. In addition, immunofluorescence staining was applied to examine von Willebrand factor (vWF)-positive vessels, the expression of cardiac troponin T (cTnT) and proliferation marker Ki67, and the number of c-kit-positive, C-X-C chemokine receptor type 4 (CXCR4)-positive, and Sca-1-positive endogenous stem cells in the infarcted area. In addition, the expression of stromal cell-derived factor (SDF)-1 and stem cell factor (SCF) was detected. EA increased the ejection fraction after MI, reduced collagen deposition and cellular apoptosis, and increased the number of blood vessels compared with an untreated model group. EA significantly promoted cellular proliferation, except for myocardial cells, and significantly increased the number of c-kit-, CXCR4- and Sca-1-positive stem cells. Moreover, the expression of SDF-1 and SCF in myocardial tissue in the EA group was significantly higher than that in the (untreated) MI group. EA appears to promote angiogenesis and reduce collagen deposition, thus improving the cardiac function of rats with MI. The underlying mechanism of action may involve endogenous stem cell mobilization mediated by SDF-1/CXCR4 and SCF/c-kit.

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.

Modified Taohong Siwu decoction improves cardiac function after myocardial ischaemia and reperfusion in rats by promoting endogenous stem cell mobilization and regulating metabolites

Context Taohong Siwu decoction (THSWD) has been shown to promote heart repair in myocardial infarction. Objective To determine the effects of modified THSWD (THSWD plus four ingredients) on myocardial ischaemia and reperfusion (I/R) injury. Materials and methods Sixty Sprague-Dawley rats were randomly divided into the I/R group and three different modified THSWD dose groups (gavage administration, 1.215, 2.43, and 4.86 g, respectively). 2,3,5-Triphenyltetrazolium chloride and Evans blue staining were used to detect the infarct area at 24 h after treatment. The serum biochemical indexes and cell apoptosis were examined to determine myocardial injury. The number of endogenous stem cells, expression of stromal dell derived factor-1 (SDF-1) and stem cell factor (SCF), and cardiac function were measured at 4 weeks. The serum was collected for metabolomic analysis. Results The high-dose modified THSWD group presented a reduced infarction area (decreased by 21.3%), decreased levels of lactate dehydrogenase and creatinine kinase, attenuated cell apoptosis, and enhanced superoxide dismutase activity in early stage I/R compared with other groups. The serum SCF and SDF-1 levels were higher in the high-dose group than in the I/R group. At 4 weeks, the infarct size and collagen content were the lowest, and the ejection fraction and fractional shortening values were the highest in the high-dose group. Moreover, high-dose modified THSWD affected the metabolism of phosphonate and phosphonate, taurine, and hypotaurine. Conclusions Endogenous stem cell mobilization and metabolic regulation were related to the cardioprotection of modified THSWD. We provided a new strategy and direction for the treatment of cardiovascular diseases with traditional Chinese medicine.

Can mobilization of bone marrow stem cells be an alternative regenerative therapy to stem cell injection in a rat model of chronic kidney disease?

Chronic kidney disease (CKD) is a priority health problem affecting 36% of Egyptians. Adipose‐derived mesenchymal stem cells (ADMSCs) have multidifferentiation capacity and the ability to restore several types of cells including damaged renal cells. Granulocyte colony‐stimulating factor (G‐CSF) is known to mobilize hematopoietic stem cells from bone marrow to the peripheral circulation. The aim of this study was to compare the effect of endogenous CD34+ cells mobilization and exogenous ADMSCs administration in the treatment of a rat model of adriamycin (ADR)‐induced CKD. A total of 48 male albino rats of the local strain (200 ± 50 g) were equally divided into four groups: control negative, ADR (control positive), ADMSCs group, and G‐CSF group. Six rats from each group were sacrificed after 4 weeks and the other 6 after 12 weeks. Renal function was assessed frequently by measuring serum creatinine, albumin, urea, 24‐h urinary protein level, and hemoglobin level throughout the study. Oxidative stress markers malondialdehyde (MDA) and total antioxidant (TAO) were measured on day 28. CD‐34+ cell percentage was measured on day 9. After the sacrification of the rats, kidneys were removed for histopathological assessment. Results revealed that both ADMSCs and G‐CSF significantly improved serum creatinine, albumin, urea, 24‐h urinary protein level, and histopathological damage score, with the G‐CSF‐treated group showing better improvement in 24‐h urinary protein level, serum albumin, and histopathological damage score compared with ADMSCs‐treated group. The G‐CSF group also had significantly higher levels of CD34+ cells. Oxidative stress markers (MDA and TAO) levels were significantly improved with both therapies. We conclude that mobilization of endogenous hematopoietic stem cells by G‐CSF is more effective than exogenously injected ADMSCs in protecting the kidneys against AD‐induced toxicity.

Combined Treatment with Insulin-Like Growth Factor 1 and AMD3100 Improves Motor Outcome in a Murine Model of Neonatal Hypoxic-Ischemic Encephalopathy

Stem cell transplantation is a promising intervention for neonatal hypoxic-ischemic encephalopathy (HIE); however, universal feasibility and safety have not been thoroughly evaluated. AMD3100 and insulin-like growth factor 1 (IGF1) mobilize progenitor cells into peripheral circulation. The objective of this study was to assess the short-term efficacy of inducing endogenous stem cell mobilization after injury in a model of neonatal HIE. Postnatal day 9 CD1 pups received sham surgery or unilateral carotid artery ligation and 30 min of hypoxia followed by saline, AMD3100, IGF1, or both agents. Intraperitoneal injections of 5-ethynyl-2′-deoxy­uridine (EdU) and 5-bromo-2′-deoxyuridine were used to ­label replicating progenitor cells. At P14, animals underwent rotarod testing, and the brains were sectioned for area measurements and immunofluorescence staining. Comparisons were made using one-way analysis of variance. Spearman’s rho was calculated to assess correlation between rotarod results and markers of brain injury. Pups treated with both agents had improved rotarod performance (p = 0.02) and increased EdU+ progenitor cells in the subgranular zone (SGZ) compared to injured controls (p = 0.10). An increase in active cells within the SGZ was correlated with improved rotarod performance (r = 0.84, p = 0.04). There were no differences in overall injury score or in brain area or number of activated cells in the subventricular zone between the treatment groups. Combined treatment with AMD3100 and IGF1 shows promise for decreasing brain injury and improving motor function in pups after HIE which correlated with changes in the number of active progenitor cells in the SGZ.

Effects and Mechanism of Action of Neonatal Versus Adult Astrocytes on Neural Stem Cell Proliferation After Traumatic Brain Injury.

Due to the limited capacity of brain tissue to self-regenerate after traumatic brain injury (TBI), the mobilization of endogenous neural stem cells (NSCs) is a popular research topic. In the clinic, the neurogenic abilities of adults versus neonates vary greatly, which is likely related to functional differences in NSCs. Recent studies have demonstrated that the molecules secreted from astrocytes play important roles in NSC fate determination. In this study, conditioned media (CM) derived from neonatal or adult rat astrocytes, which were unstimulated or stimulated by lipopolysaccharide (LPS), were prepared to treat NSCs. Our results revealed that neonatal rat astrocytes can significantly promote the proliferation of NSCs, compared with adult rat astrocytes, regardless of whether or not they were stimulated by LPS. Furthermore, we used mass spectrometry to detect the constituents of the CM from each group. We analyzed and screened for a protein, Tenascin-C (TNC), which was highly expressed in the neonatal group but poorly expressed in the adult group. We found that TNC can bind to the NSC surface epidermal growth factor receptor and promote proliferation through the PI3K-AKT pathway in vitro. Additionally, we confirmed in vivo that TNC can promote damage repair in a rat model of TBI, through enhancing the proliferation of endogenous NSCs. We believe that these findings provide a mechanistic understanding of why neonates show better neuroregenerative abilities than adults. This also provides a potential future therapeutic target, TNC, for injury repair after TBI. Stem Cells 2019;37:1344-1356.

PEGylated substance P augments therapeutic angiogenesis in diabetic critical limb ischemia

Substance P (SP) is a therapeutic peptide that has been widely used to induce angiogenesis and tissue regeneration. However, its therapeutic efficacy is often limited due to rapid degradation in vivo and a short half-life (˜1min) after systemic administration. In the present study, we chemically modified SP with polyethylene glycol (PEG) to generate long-lasting formulations with increased stability and extended retention time in vivo and evaluated their ability to enhance therapeutic angiogenesis. Compared to the unmodified SP, PEGylated SP (PEG-SP) exhibited significantly increased half-life in vivo (˜360-fold increase in normal mouse and ˜120-fold increase in diabetic mouse). Systemic injection of PEG-SP led to a marked increase in therapeutic efficacy and angiogenesis in diabetic hindlimb ischemia, as evident from the remarkable improvement in salvage of ischemic limb and recovery of blood perfusion in diabetic mice with limb ischemia. These formulations increased endogenous stem cell mobilization to the injured site and modulated the immune system to increase microvessel formation and reduce systemic inflammation. Importantly, PEGylation efficiently reduced the injection doses of SP while still maintaining its therapeutic efficacy. To conclude, our study demonstrated that PEG-SP formulations exhibited an improved in vivo pharmacokinetic profile with enhanced efficacy and clinically acceptable treatment regimens, thus acting as a potent therapeutic for diabetic ischemia and inflammation.

Stem Cell Mobilization Is Lifesaving in a Large Animal Preclinical Model of Acute Liver Failure.

Acute liver failure (ALF) affects 2000 Americans each year with no treatment options other than liver transplantation. We showed previously that mobilization of endogenous stem cells is protective against ALF in rodents. The objective of this study was to assess whether stem cell mobilizing drugs are lifesaving in a large animal preclinical model of ALF, to assess readiness for a clinical trial. Male Yorkshire pigs (14-18 kg) were divided into 2 groups, control (n = 6) and treatment (n = 6). All pigs received an intravenous bolus of the hepatotoxin D-galactosamine (0.5 g/kg) via central line and were followed up until death or day 28. Treated animals received simultaneous intramuscular injection of plerixafor (1 mg/kg) and G-CSF (2 μg/kg) at baseline, 24 and 48 hours after toxin infusion to mobilize endogenous stem cells, as previously described. Control animals received saline. All control animals (6/6) succumbed to liver failure within 91 hours, confirmed by clinical, biochemical, and histopathological evidence of ALF. In the treatment group (5/6) animals survived indefinitely despite comparable biochemical changes during the first 48 hours (P = 0.003). White blood cell count increased by a mean of 4× in the treated group at the peak of mobilization (P = 0.0004). Stem cell mobilizing drugs were lifesaving in a preclinical large animal model of ALF. Since no therapeutic options other than liver transplantation are currently available for critically ill patients with ALF, a multicenter clinical trial is warranted.

Pharmacological Mobilization and Recruitment of Endogenous Stem Cells Prevents Postsurgical Intra-Abdominal Adhesion in Rats

Background: Postsurgical adhesions are a very common complication causing various symptoms from pain to bowel obstruction. We have developed a stem cell mobilizing strategy that enables long-term liver and kidney allograft survival without sustained immunosuppression in animals using a combination of AMD3100 and low-dose FK506 (AF). Serendipitously we have noted a subjective decrease in adhesion formation in animals with AF combination treatment. The purpose of this study was to evaluate the effect of a new stem cell mobilizing strategy on preventing postsurgical adhesion formation in rats. Methods: Abdominal adhesions were induced by creating suture knots on the parietal peritoneum in Lewis rats. Animals were divided randomly into four experimental groups and received subcutaneous injections of saline, single drug or AF combination every other day for 10 days. On postoperative day 14, animals were euthanized and the severity of adhesions were evaluated and scored blindly by five individual surgeons. Results: Most animals treated with saline or single drug exhibited severe peritoneal adhesions around sites of suture knots. AF combination significantly reduced the formation of peritoneal adhesions, 64% animals (7/11) showed few or mild adhesion and no animal showed severe peritoneal adhesions. Searching for mechanisms, we found AF treatment dramatically increased SDF-1 expressing cells, HGF expressing Ym1 M2 macrophages and CD133 stem cells in the injury sites of peritoneal surface at day 5 post-operation. Conclusion: Pharmacological mobilization and recruitment of endogenous stem cells using AF combination significantly reduced postsurgical intra-abdominal adhesions in rats. These findings suggest a novel therapeutic approach to preventing postsurgical adhesions in patients undergoing abdominal or pelvic surgery. Funding Statement: This work was supported by a start-up fund from the surgical department at Johns Hopkins University. Declaration of Interests: None of the authors has a financial interest in any of the products, or drugs mentioned in this manuscript. Ethics Approval Statement: Animals were maintained in a pathogen-free facility of Johns Hopkins University School of Medicine and all animal experiments were performed in accordance with the United States National Institutes of Health (NIH) guidance. All animal protocols were reviewed and approved by the Johns Hopkins University Animal Care and Use Committee.

Pharmacological Mobilization of Endogenous Bone Marrow Stem Cells Promotes Liver Regeneration after Extensive Liver Resection in Rats

Rapid regeneration of the remnant liver is critical for preventing liver failure and promoting recovery after extensive liver resection. Numerous studies have demonstrated the involvement of bone marrow-derived stem cells in liver regeneration and the potential benefits of bone marrow stem cell therapy. To avoid the preparation of stem cells, we proposed in this study to mobilize endogenous bone marrow stem cells pharmacologically with a combination of AMD3100 (A), an antagonist of CXCR4 and low-dose FK506 (F). Here we show that AF combination therapy significantly increased lineage negative (Lin-) CD34+ and Lin-CD133+ stem cells in peripheral blood and enhanced recruitment of CD133+ cells into the remnant liver in a rat model of 85% partial hepatectomy. Recruiting CD133+ stem cells in the remnant liver was associated with increased proliferation of hepatic oval cells and paralleled the increased SDF-1, CXCR4 and HGF expression. Importantly, AF combination therapy increased the number of Ki67 positive hepatocytes and BrdU incorporation in the remnant liver and improved serum levels of albumin. Our results demonstrate that pharmacological mobilization of endogenous bone marrow stem cells with AF combination therapy can enhance endogenous stem cell mobilization to promote liver regeneration and improve liver function after extensive hepatectomy.

High-density lipoprotein-mimicking nanodiscs carrying peptide for enhanced therapeutic angiogenesis in diabetic hindlimb ischemia

Therapeutic strategies using endogenous stem cell mobilizer can provide effective cell-free therapy for addressing various ischemic diseases. In particular, substance P (SP) exhibited therapeutic regeneration by facilitating mobilization of endogenous stem cells from bone marrow to the injured sites. However, its therapeutic effect has been limited due to short half-life and rapid degradation of administered SP peptides in vivo. Here we sought to develop high-density lipoprotein (HDL)-mimicking nanodiscs conjugated with SP (HDL-SP) in order to increase the in vivo half-life, bone marrow targeting, and therapeutic efficacy of SP for the treatment of diabetic peripheral ischemia. Conjugation of SP onto HDL nanodisc led to remarkable ∼3215- and ∼1060-fold increase in the ex vivo and in vivo half-lives of SP, respectively. Accordingly, HDL-SP nanodiscs improved retention of SP in bone marrow after systemic administration, leading to efficient mobilization of stem cells from bone marrow into blood circulation and reduction of systemic inflammation. Consequently, nanodisc based SP peptide delivery promoted blood vessel formation, blood perfusion recovery and markedly improved limb salvage in diabetic hindlimb ischemia model relative to administration of free SP without nanodisc modification. Therefore, HDL-SP nanodisc can provide a novel strategy for the treatment of diabetic ischemia and HDL nanodisc modification could be potentially useful for the extension of plasma circulation of other labile peptides.

Histological Study on the Protective Effect of Endogenous Stem Cell Mobilization in Busulfan-Induced Testicular Injury in Albino Rats.

Background:Testicular damage is one of the most hazardous effects of chemotherapy as it is frequently associated with oligozoospermia and azoospermia.Aim of the Work:This study aimed at evaluating the protective effect of hematopoietic stem cell mobilization by granulocyte colony-stimulating factor (G-CSF) in a rat model of busulfan-induced testicular injury.Materials and Methods:Twenty-four adult albino rats were divided into four groups: group I, the control, Group II: rats received two doses of busulfan (each 15 mg/kg) intraperitoneally (IP) with 14 days interval, Group III: rats received busulfan and left untreated, and Group IV received busulfan IP then G-CSF (70 μg/kg/day) subcutaneously for 5 consecutive days. Testicular sections were stained with H and E and immunohistochemically for CD34, proliferating cell nuclear antigen (PCNA) and caspase-3, and semithin sections were stained with toluidine blue.Results:Groups II and III showed loss of the normal histological architecture of the testis and spermatogenic cells, with increased apoptosis confirmed by significantly increased caspase-3 and significantly decreased PCNA immunoexpression. While Group IV revealed improved testicular histology, decreased apoptosis, and increased proliferative capacity of spermatogenic cells. This was confirmed by significantly decreased caspase-3 immunoexpression and increased PCNA immunoreaction.Conclusion:Mobilization of stem cells with G-CSF was found to improve the testicular histology following busulfan chemotherapy in albino rats.

Honey can repairing damage of liver tissue due to protein energy malnutrition through induction of endogenous stem cells.

Aim:This study was to evaluate effect of honey in repairing damage of liver tissue due to energy protein malnutrition and in mobilization of endogenous stem cells.Materials and Methods:Male mice model of degenerative liver was obtained through food fasting but still have drinking water for 5 days. It caused energy protein malnutrition and damage of liver tissue. The administration of 50% (v/v) honey was performed for 10 consecutive days, while the positive control group was fasted and not given honey and the negative control not fasted and without honey. Observations of regeneration the liver tissue based on histologically examination, observation of Hsp70 expression, and homing signal based on vascular endothelial growth factor-1 (VEGF-1) expression using immunohistochemistry technique. Observation on expression of CD34 and CD45 as the marker of auto mobilization of hematopoietic stem cells using flow cytometry technique.Results:There is regeneration of the liver tissue due to protein energy malnutrition, decrease of Hsp70 expression, increase of VEGF-1 expression, and high expression of CD34 and CD45.Conclusion:Honey can improve the liver tissue based on: (1) Mobilization of endogenous stem cells (CD34 and CD45); (2) Hsp70 and VEGF-1 expressions as regeneration marker of improvement, and (3) regeneration histologically of liver tissue

Prevention of Donor Specific Antibody Production after Skin Allografting by Mobilization of Endogenous Stem Cells Using a Combination of AMD3100 and Low-dose FK506 in Rats

Background: We have developed a stem cell mobilizing strategy that enables long-term liver and kidney allograft survival without sustained immunosuppression in small and large animals using a safe combination of two FDA approved drugs AMD3100 and low-dose FK506 (AF). Furthermore, no increase in serum DSA levels was detected in animals displaying long-term survival even after donor skin grafts were rejected. Therefore, the purpose of this study is to determine if AF combination treatment prevents de novo DSA production in a rat model of skin allograft rejection. Methods: Split thickness skin allografts from Dark Agouti (DA, RT1a) rats were transplanted into adult Lewis (RT11) recipients. Recipient animals were randomly divided into AF treatment group (AMD3100 1 mg/kg and FK506 0.1 mg/kg, s.c., every other day for 14 days) and control group (same volume of saline, s.c.). Serum levels of DSA including both IgG and IgM were measured by flow cytometry at 14 days, 1 and 2 months after skin transplantation. The sensitization to donor antigens in Lewis rats at 2 months after skin allografting was further confirmed by transplanting donor DA kidneys. Full dose FK506 (1 mg/kg/day, s.c) was given to prevent acute cellular rejection after kidney transplantation. Results: Skin allografts were rejected in 8–10 days after transplantation in both groups. Serum levels of DSA-IgG increased 6 to 10 folds in control animals (n = 10), but only 2 to 3 folds in animals treated with AF combination (n = 11) at 1 month and remained at similar levels at 2 months after skin transplantation. All control animals (n = 5) died within 7 days after kidney transplantation. DSA deposition and AMR in kidney allografts were confirmed with signs of IgG deposition in and around glomeruli with C4d deposition on peritubular capillaries. In contrast, about 64% (7/11) animals with AF treatment after skin allografting survived over three weeks without antibody mediated rejection (AMR) and no increase in serum levels of DSA at 14 days after kidney transplantation. Conclusion: Mobilizing endogenous stem cells with AF combination treatment does not prolong skin allograft survival but prevents de novo DSA production after allograft rejection. AF treatment may inhibit B cell sensitization, prevent de novo DSA production and improve long-term allograft function after organ transplantation.

THE THERAPEUTIC POTENTIAL OF STIMULATING ENDOGENOUS STEM CELL MOBILIZATION.

The past few years have seen extensive interest in treatment of various diseases with adult stem cells (ASC). This paper will not discuss umbilical cord or adipose tissue derived stem cells, but rather peripheral blood stem cells (PBSC). We will demonstrate that one of the natural roles of stem cells is to participate in tissue repair both due to injury or degenerative disease. We will review the mechanisms involved with stem cell release and activation and present two new natural triggers for this release and possible differentiation. The clinical relevance of mobilizing endogenous bone marrow derived stem cells would be to increase the number migrating into damaged organs, becoming affective cells and contributing to tissue repair. This approach overcomes the problems of growing autologous stem cell cultures and their implantation. It also may release other progenitor cells that appears to be playing a vital role in organ regeneration. We present examples of tissue repair using these new modalities. Part of this paper was first presented at the international conference of acupuncture and electrotherapeutics held at Columbia University Oct. 2013. Since then the field has exploded and we will try to include some of the most relevant discoveries.

Su1228 - Pharmacological Mobilization of Endogenous Stem Cells Prevents Postsurgical Intra-Abdominal Adhesion in Rats

Su1228 - Pharmacological Mobilization of Endogenous Stem Cells Prevents Postsurgical Intra-Abdominal Adhesion in Rats

Combination of endogenous neural stem cell mobilization and lithium chloride treatment for hydrocephalus following intraventricular hemorrhage.

As there are multiple factors causing hydrocephalus subsequent to intraventricular hemorrhage (IVH), it is difficult to achieve the best treatment effect using a single drug alone. In the present study, the protective effect of combination treatment with granulocyte-colony stimulating factor (G-CSF) and lithium chloride against hydrocephalus after IVH was investigated. A total of 130 adult male Sprague-Dawley rats were divided into five groups, including the IVH control, G-CSF treatment, lithium chloride treatment, combination treatment and sham surgery groups. An IVH rat model was established in order to examine the effect of combination treatment on hydrocephalus incidence. A TUNEL assay was performed to detect neuronal apoptosis in the five groups. In addition, the protein expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were detected by western blot analysis. The differentiation of nerve cells in the brain tissue obtained from the five rat groups was also determined with double immunofluorescence staining. The results demonstrated that administration of G-CSF or lithium chloride alone was able to only partly relieve the incidence of hydrocephalus after IVH. By contrast, combination treatment with G-CSF and lithium chloride significantly attenuated the development of hydrocephalus following IVH. TUNEL assay showed that neuronal apoptosis was significantly reduced by the combination treatment with G-CSF and lithium chloride. Furthermore, the expression of Bcl-2 was upregulated, whereas Bax expression was downregulated in the combination treatment group. The results also detected the highest expression of BrdU/GFAP, BrdU/NeuN and BrdU/PSA-NCAM in the combination treatment group. In conclusion, the combination of endogenous neural stem cell mobilization (using G-CSF) and lithium chloride treatment resulted in highly reduced incidence of hydrocephalus after IVH by inhibiting neuronal apoptosis.

Activation of Endogenous Cardiac Stem Cells by Apelin-13 in Infarcted Rat Heart.

Our previous study demonstrated that the apelin-APJ pathway contributed to myocardial regeneration and functional recovery after bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation during the differentiation of BM-MSCs into cardiomyogenic cells in acute myocardial infarction (AMI) rat models. However, the underlying mechanisms by which apelin promotes cardiac repair and functional recovery have not been completely clarified. In the present study, we investigated whether apelin could mobilize and activate endogenous cardiac stem cells and progenitors, thereby mediating regeneration and repair of the myocardium after AMI in rat models. Six-week-old male Sprague-Dawley rats underwent AMI and received apelin-13 (200 ng, n = 10) or an equivalent volume of saline by intramyocardial injection (n = 10); there was also a sham operation group (n = 8). Proliferation of endogenous cardiac stem cells was analyzed by immunofluorescence staining in rat infarcted myocardium, and heart function was evaluated by echocardiography at 28 days after apelin-13 injection. Treatment with apelin-13 led to a significant increase of Ki-67+-c-kit+/Sca-1+/Flk-1+ endogenous cardiac stem or progenitor cells in the border zone and infarct zone of rat hearts at 28 days after myocardial infarction (MI). Significant increases in the expression of c-kit, Sca-1, and Flk-1 on both levels of transcription and translation were confirmed by real-time polymerase chain reaction (RT-PCR) and Western blot. Treatment of apelin-13 also resulted in a significant reduction of infarct size and improvement of cardiac function post-MI. We conclude that apelin-13 is able to enhance mobilization, survival, and proliferation of endogenous myocardial stem cells in the injured heart, providing a novel mechanistic explanation for how apelin-13 might repair the heart and improve cardiac function. Thus, apelin-13 or pharmacological agonists of the APJ receptor could act as novel therapies for heart regeneration.