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Locally Transplanted CD34+ Bone Marrow–Derived Cells Contribute to Vascular Healing After Vascular Injury. Transplant Proc 2017; 49:1467-1476. [DOI: 10.1016/j.transproceed.2017.01.081] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 01/24/2017] [Indexed: 01/13/2023]
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Systemic Transplantation of Bone Marrow Mononuclear Cells Promotes Axonal Regeneration and Analgesia in a Model of Wallerian Degeneration. Transplantation 2017; 101:1573-1586. [DOI: 10.1097/tp.0000000000001478] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Endo K, Hori T, Jobara K, Hata T, Tsuruyama T, Uemoto S. Pretransplant replacement of donor liver grafts with recipient Kupffer cells attenuates liver graft rejection in rats. J Gastroenterol Hepatol 2015; 30:944-51. [PMID: 25532540 DOI: 10.1111/jgh.12872] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/16/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Rejection of liver grafts is a difficult issue that has not been resolved. Preoperative replacement of liver cells in the graft with cells from the intended recipient may attenuate rejection. We investigated whether preoperative transplant of recipient bone marrow cells (BMCs) to the donor replaced liver allograft cells and attenuated rejection. METHODS We used a rat model of allogeneic liver transplant (LT) from Dark Agouti (DA) to Lewis (LEW) rats. In BMC group, DA rats received BMC transplants from LacZ-transgenic LEW rats at 1 week before LT. In the control group, DA rats received no preoperative treatment. We evaluated graft damage at 7 days after LT and the survival of the recipient rats. RESULTS Rats in the BMC group experienced prolonged survival that was abrogated by the administration of gadolinium chloride to donors at 24 h before LT. Serum concentrations of total bilirubin and hyaluronic acid on day 7 were significantly lower in the BMC group, and histopathological analyses revealed that rejection of the liver graft was attenuated. X-gal staining and immunohistostaining of the liver graft revealed that BMCs engrafted in the sinusoidal space differentiated into Kupffer cells. CONCLUSIONS Preoperative transplant of recipient BMCs to LT donors replaced donor Kupffer cells and attenuated post-LT rejection, indicating that this strategy may increase the success of LT.
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Affiliation(s)
- Kosuke Endo
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Cheng CC, Chung CA, Su LC, Chien CC, Cheng YC. Osteogenic differentiation of placenta-derived multipotent cells in vitro. Taiwan J Obstet Gynecol 2015; 53:187-92. [PMID: 25017264 DOI: 10.1016/j.tjog.2014.04.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Accepted: 08/15/2012] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE Stem cells offer great potential for clinical therapeutic use because of their ability to rejuvenate and to differentiate into numerous types of cells. We isolated multipotent cells from the human term placenta that were capable of differentiation into cells of all three germ layers. MATERIALS AND METHODS We examined the ability of these placenta-derived multipotent cells (PDMCs) to differentiate into osteoblasts (OBs) or OB-like cells. The PDMCs were treated with osteogenic medium (OM) consisting of dexamethasone, β-glycerol phosphate, and ascorbic acid. At sequential time intervals (0 day, 3 days, 6 days, 9 days, and 12 days) we measured several parameters. These included alkaline phosphatase (ALP) activity, alizarin red staining (ARS) to measure calcium deposition, messenger RNA (mRNA) expressions of osteogenesis-related transcription factor (Cbfa1), and calcium coordination protein (osteocalcin). These variables were used as indicators of PDMC osteodifferentiation. RESULTS We showed that ALP activity in the early stage of differentiation and calcium deposition were both significantly increased in PDMCs after OM induction. Moreover, the Cbfa1 and osteocalcin gene expressions were upregulated. The results suggested that OM induced an osteodifferentiation potential in PDMCs. CONCLUSION PDMC-derived osteocytes provide a useful model to evaluate the mechanisms of key biomolecules and bioengineering processes.
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Affiliation(s)
- Chih-Chien Cheng
- Department of Mechanical Engineering, National Central University, Jhongli, Taiwan; Department of Obstetrics and Gynecology, Sijhih Cathay General Hospital, Taipei, Taiwan; Department of Obstetrics and Gynecology, Taipei Medical University, Taipei, Taiwan
| | - Chih-Ang Chung
- Department of Mechanical Engineering, National Central University, Jhongli, Taiwan; Institute of Biomedical Engineering, National Central University, Jhongli, Taiwan
| | - Li-Chiu Su
- Cathay Medical Research Institute, Cathay General Hospital, Taipei, Taiwan
| | - Chih-Cheng Chien
- Institute of Biomedical Engineering, National Central University, Jhongli, Taiwan; School of Medicine, Fu Jen Catholic University, Taipei, Taiwan; Department of Anesthesiology, Sijhih Cathay General Hospital, Sijhih City, Taipei, Taiwan
| | - Yu-Che Cheng
- Institute of Biomedical Engineering, National Central University, Jhongli, Taiwan; Cathay Medical Research Institute, Cathay General Hospital, Taipei, Taiwan.
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De Angelis B, Gentile P, Orlandi F, Bocchini I, Di Pasquali C, Agovino A, Gizzi C, Patrizi F, Scioli MG, Orlandi A, Cervelli V. Limb rescue: a new autologous-peripheral blood mononuclear cells technology in critical limb ischemia and chronic ulcers. Tissue Eng Part C Methods 2015; 21:423-35. [PMID: 25341088 DOI: 10.1089/ten.tec.2014.0245] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
INTRODUCTION Therapeutic angiogenesis by autologous-peripheral blood mononuclear cells (A-PBMNC) implantation has been shown to be a safe and effective treatment for critical limb ischemia (CLI). We herein report our investigation of the long-term efficacy of implantation of A-PBMNC produced by selective filtration to treat patients with CLI, for which surgical bypass and/or percutaneous transluminal angioplasty are not possible. MATERIALS AND METHODS This is a prospective, and not a randomized, study based on a treated group who did not respond to conventional therapy (n=43) when implanted with A-PBMNC cells versus a historically matched control group. Patients of both groups were suffering from CLI Fontaine scale IV with chronic ulcers and various accompanying conditions (diabetes, heart disease, kidney failure, etc.). Treated patients were implanted with 12 mL of A-PBMNC, 0.2-0.3 mL for each bolus, collected by selective filtration from 120 mL of peripheral blood in the ischemic area of the limbs. Patients were not mobilized by granulocyte colony-stimulating factor, and the A-PBMNC treatment was repeated for a maximum of three times. RESULTS The A-PBMNC-treated group showed a statistically significant improvement of limb rescue of 95.3% versus 52.2% of the control group (p<0.001), and the result had been maintained for 2 years. The A-PBMNC group also showed reduction in pain at rest, increased maximum walking distance, and healing of the wound, which led to an overall improvement in the quality of life. Post-treatment radiological studies showed an improvement of vascularization with the formation of new collateral and by histological findings. Within 2 years of follow-up, none of the patients whom we treated showed any major or systemic adverse effects. CONCLUSION The local injection of A-PBMNC showed striking early and long-term effects together with a favorable safety profile, significantly decreasing the risk of amputation. Our results are comparable with published data obtained by injection of bone marrow mononuclear cells, but with a lot less invasive approach. Moreover the intraoperative selective filtration system we used is fast, safe, not operator dependent, and easy to use in a sterile operating theatre. This system aims to produce fresh A-PBMNC as a valuable treatment option, particularly for those difficult patients who cannot undergo revascularization.
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Affiliation(s)
- Barbara De Angelis
- 1 Department of Plastic and Reconstructive Surgery, University of Rome Tor Vergata , Rome, Italy
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Pala HG, Pala EE, Artunc Ulkumen B, Aktug H, Yavasoglu A, Korkmaz HA, Erbas O. The Protective Effect of Granulocyte Colony-Stimulating Factor on Endometrium and Ovary in a Rat Model of Diabetes Mellitus. Gynecol Obstet Invest 2014; 78:94-100. [DOI: 10.1159/000363239] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 04/24/2014] [Indexed: 11/19/2022]
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Abstract
Liver transplantation remains the only definitive treatment for liver failure and is available to only a tiny fraction of patients with end-stage liver diseases. Major limitations for the procedure include donor organ shortage, high cost, high level of required expertise, and long-term consequences of immune suppression. Alternative cell-based liver therapies could potentially greatly expand the number of patients provided with effective treatment. Investigative research into augmenting or replacing liver function extends into three general strategies. Bioartificial livers (BALs) are extracorporeal devices that utilize cartridges of primary hepatocytes or cell lines to process patient plasma. Injection of liver cell suspensions aims to foster organ regeneration or provide a missing metabolic function arising from a genetic defect. Tissue engineering recreates the organ in vitro for subsequent implantation to augment or replace patient liver function. Translational models and clinical trials have highlighted both the immense challenges involved and some striking examples of success.
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Affiliation(s)
- Joseph P Vacanti
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Surgery, Massachusetts General Hospital, 55 Fruit St, WRN 1151, Boston, Massachusetts 02114; Department of Pediatric Surgery, MassGeneral Hospital for Children, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
| | - Katherine M Kulig
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Surgery, Massachusetts General Hospital, 55 Fruit St, WRN 1151, Boston, Massachusetts 02114; Department of Pediatric Surgery, MassGeneral Hospital for Children, Boston, Massachusetts
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Continued sustained release of VEGF by PLGA nanospheres modified BAMG stent for the anterior urethral reconstruction of rabbit. ASIAN PAC J TROP MED 2014; 6:481-4. [PMID: 23711710 DOI: 10.1016/s1995-7645(13)60078-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Revised: 04/15/2013] [Accepted: 05/15/2013] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE To study the biocompatibility and neovascularization of the PLGA nanospheres wrapped with vascular endothelial growth factor (VEGF), which can improve bladder acellular matrix graft (BAMG) with local continuous release of VEGF. METHODS A total of 18 rabbit model (length of stenosis: 3 cm) with anterior urethral stricture were used as experimental animals and divided into three groups. Group A as the control group: Simple BAMG scaffold materials for urethral reconstruction. Group B as the blank group: PLGA microspheres modified BAMG for urethral reconstruction. Group C: PLGA conjugated with VEGF and modified BAMG for the urethral reconstruction. All rabbits underwent urethral angiography after 7 days, 15 days, 1 month and 3 months after the operation, and one rabbit in each group was sacrificed to be prepared for the organization histologic examination, HE staining, masson staining, CD31, 34 and a-SAM immunohistochemical detection in the repaired sites. RESULTS In group A, significant urethral restenosis occurred in two rabbits after 15 days of the operation, HE and masson staining showed a lot of collagen arranged in the repaired sites, and there were a large number of inflammatory cell infiltration, and there were also CD31, 34 in the repaired sites. a-SAM microvascular tag count showed a small amount of microvascular; Group B showed anastomotic restenosis, HE and masoon staining showed inflammatory cell infiltration and collagen deposition; Group C: urethrography showed lumen patency. There were a small amount of inflammatory cell infiltration after 7 and 15 days after the operation, and there were also CD31, 34 in the repaired sites. The a-SAM microvascular tag count showed many microvascular. And the difference was significant. CONCLUSIONS Anterior urethral reconstruction with sustained-release of VEGF by PLGA nanospheres modified BAMG stents can reduce postoperative restenosis. It can also reduce collagen deposition and scar formation, promote angiogenesis of the repair tissue; therefore it in valuable in the tissue-engineered urethral reconstruction.
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Sun XT, Yuan XW, Zhu HT, Deng ZM, Yu DC, Zhou X, Ding YT. Endothelial precursor cells promote angiogenesis in hepatocellular carcinoma. World J Gastroenterol 2012; 18:4925-33. [PMID: 23002366 PMCID: PMC3447276 DOI: 10.3748/wjg.v18.i35.4925] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2011] [Revised: 05/16/2012] [Accepted: 05/26/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of bone marrow-derived endothelial progenitor cells (EPCs) in the angiogenesis of hepatocellular carcinoma (HCC).
METHODS: The bone marrow of HCC mice was reconstructed by transplanting green fluorescent protein (GFP) + bone marrow cells. The concentration of circulating EPCs was determined by colony-forming assays and fluorescence-activated cell sorting. Serum and tissue levels of vascular endothelial growth factor (VEGF) and colony-stimulating factor (CSF) were quantified by enzyme-linked immunosorbent assay. The distribution of EPCs in tumor and tumor-free tissues was detected by immunohistochemistry and real-time polymerase chain reaction. The incorporation of EPCs into hepatic vessels was examined by immunofluorescence and immunohistochemistry. The proportion of EPCs in vessels was then calculated.
RESULTS: The HCC model was successful established. The flow cytometry analysis showed the mean percentage of CD133CD34 and CD133VEGFR2 double positive cells in HCC mice was 0.45% ± 0.16% and 0.20% ± 0.09% respectively. These values are much higher than in the sham-operation group (0.11% ± 0.13%, 0.05% ± 0.11%, n = 9) at 14 d after modeling. At 21 d, the mean percentage of circulating CD133CD34 and CD133VEGFR2 cells is 0.23% ± 0.19%, 0.25% ± 0.15% in HCC model vs 0.05% ± 0.04%, 0.12% ± 0.11% in control. Compared to the transient increase observed in controls, the higher level of circulating EPCs were induced by HCC. In addition, the level of serum VEGF and CSF increased gradually in HCC, reaching its peak 14 d after modeling, then slowly decreased. Consecutive sections stained for the CD133 and CD34 antigens showed that the CD133+ and CD34+ VEGFR2 cells were mostly recruited to HCC tissue and concentrated in tumor microvessels. Under fluorescence microscopy, the bone-marrow (BM)-derived cells labeled with GFP were concentrated in the same area. The relative levels of CD133 and CD34 gene expression were elevated in tumors, around 5.0 and 3.8 times that of the tumor free area. In frozen liver sections from HCC mice, cells co-expressing CD133 and VEGFR2 were identified by immunohistochemical staining using anti-CD133 and VEGFR2 antibodies. In tumor tissue, the double-positive cells were incorporated into vessel walls. In immunofluorescent staining. These CD31 and GFP double positive cells are direct evidence that tumor vascular endothelial cells (VECs) come partly from BM-derived EPCs. The proportion of GFP CD31 double positive VECs (out of all VECs) on day 21 was around 35.3% ± 21.2%. This is much higher than the value recorded on day 7 group (17.1% ± 8.9%). The expression of intercellular adhesion molecule 1, vascular adhesion molecule 1, and VEGF was higher in tumor areas than in tumor-free tissues.
CONCLUSION: Mobilized EPCs were found to participate in tumor vasculogenesis of HCC. Inhibiting EPC mobilization or recruitment to tumor tissue may be an efficient strategy for treating HCC.
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Abstract
BACKGROUND Liver cell transplantation and bioartificial liver may provide metabolic support of liver function temporary and are prospective treatments for patients with liver failure. Mesenchymal stem cells (MSCs) are expected to be an ideal cell source for transplantation or liver tissue engineering, however the hepatic differentiation of MSCs is still insufficient for clinical application. DATA SOURCES A PubMed search on "mesenchymal stem cells", "liver cell" and "hepatocyte differentiation" was performed on the topic, and the relevant articles published in the past ten years were reviewed. RESULTS Hepatocyte-like cells differentiated from MSCs are a promising cell source for liver regeneration or tissue engineering. Although it is still a matter of debate as to whether MSC-derived hepatocytes may efficiently repopulate a host liver to provide adequate functional substitution, the majority of animal studies support that MSCs can become key players in liver-directed regenerative medicine. However the clinical application of human stem cells in the treatment of liver diseases is still in its infancy. CONCLUSIONS Future studies are required to improve the efficacy and consistency of hepatic differentiation from MSCs. It is necessary to better understand the mechanism to achieve transdifferentiation with high efficiency. More clinical trials are warranted to prove their efficacy in the management of patients with liver failure.
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Abstract
Blood vessel formation plays a key role in both physiologic and pathologic tissue growth and healing. Thus, a thorough understanding of the mechanisms underlying neovascularization will translate into innovative clinical treatment strategies for a wide variety of disease processes. Vascular precursor/progenitor cell populations have been isolated from several different tissue types and have a rich potential for use in vascular regenerative strategies. Furthermore, levels of circulating endothelial progenitor cells (EPC) have been shown to correlate with outcomes in cardiovascular and vascular diseases. Treatment with EPC has been shown to improve functional outcomes following cardiac and peripheral vascular ischemia. Recent studies have also demonstrated a role for EPC in pediatric disease processes such as retinopathy of prematurity and bronchopulmonary dysplasia. In addition, many of the drugs utilized to treat vascular disease impact EPC mobilization and function. Importantly, the type of vascular injury appears to dictate the mechanism of neovascularization, highlighting the importance of carefully selected vascular regenerative strategies.
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Abstract
While many murine models have been developed to study adult disease, animal research focused on neonatal and pediatric medicine has been limited by the small size of the mouse pups. Several transplantation, injection, and implantation systems have been used to study the function and role of vascular progenitor populations in adult mice; however, such techniques have been difficult to translate into newborn animals. Herein, we describe a model of neonatal murine intravascular injections that opens opportunity to study many diseases unique to the newborn that might benefit from vascular repair strategies and regenerative medicine.
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Affiliation(s)
- Kirsten A Kienstra
- Division of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
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Agrawal V, Kelly J, Tottey S, Daly KA, Johnson SA, Siu BF, Reing J, Badylak SF. An isolated cryptic peptide influences osteogenesis and bone remodeling in an adult mammalian model of digit amputation. Tissue Eng Part A 2011; 17:3033-44. [PMID: 21740273 DOI: 10.1089/ten.tea.2011.0257] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Biologic scaffolds composed of extracellular matrix (ECM) have been used successfully in preclinical models and humans for constructive remodeling of functional, site-appropriate tissue after injury. The mechanisms underlying ECM-mediated constructive remodeling are not completely understood, but scaffold degradation and site-directed recruitment of progenitor cells are thought to play critical roles. Previous studies have identified a cryptic peptide derived from the C-terminal telopeptide of collagen IIIα that has chemotactic activity for progenitor cells. The present study characterized the osteogenic activity of the same peptide in vitro and in vivo in an adult murine model of digit amputation. The present study showed that the cryptic peptide increased calcium deposition, alkaline phosphatase activity, and osteogenic gene expression in human perivascular stem cells in vitro. Treatment with the cryptic peptide in a murine model of mid-second phalanx digit amputation led to the formation of a bone nodule at the site of amputation. In addition to potential therapeutic implications for the treatment of bone injuries and facilitation of reconstructive surgical procedures, cryptic peptides with the ability to alter stem cell recruitment and differentiation at a site of injury may serve as powerful new tools for influencing stem cell fate in the local injury microenvironment.
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Affiliation(s)
- Vineet Agrawal
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Krause P, Rave-Fränk M, Wolff HA, Becker H, Christiansen H, Koenig S. Liver sinusoidal endothelial and biliary cell repopulation following irradiation and partial hepatectomy. World J Gastroenterol 2010; 16:3928-35. [PMID: 20712054 PMCID: PMC2923767 DOI: 10.3748/wjg.v16.i31.3928] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether irradiation (IR) and partial hepatectomy (PH) may prepare the host liver for non-parenchymal cell (NPC) transplantation.
METHODS: Livers of dipeptidyl peptidase IV (DPPIV)-deficient rats were pre-conditioned with external beam IR (25 Gy) delivered to two-thirds of the right liver lobules followed by a one-third PH of the untreated lobule. DPPIV-positive liver cells (NPC preparations enriched for liver sinusoidal endothelial cells (LSECs) and hepatocytes) were transplanted via the spleen into the recipient livers. The extent and quality of donor cell engraftment and growth was studied over a long-term interval of 16 wk after transplantation.
RESULTS: Host liver staining demonstrated 3 different repopulation types. Well defined clusters of donor-derived hepatocytes with canalicular expression of DPPIV were detectable either adjacent to or in between large areas of donor cells (covering up to 90% of the section plane) co-expressing the endothelial marker platelet endothelial cell adhesion molecule. The third type consisted of formations of DPPIV-positive duct-like structures which co-localized with biliary epithelial CD49f.
CONCLUSION: Liver IR and PH as a preconditioning stimulus enables multiple cell liver repopulation by donor hepatocytes, LSECs, and bile duct cells.
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Stutchfield BM, Forbes SJ, Wigmore SJ. Prospects for stem cell transplantation in the treatment of hepatic disease. Liver Transpl 2010; 16:827-36. [PMID: 20583084 DOI: 10.1002/lt.22083] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Stem cell therapy has the potential to provide a valuable adjunct to the management of hepatic disease. Preclinical studies have demonstrated a range of endogenous repair processes that can be exploited through stem cell therapy. Initial translational studies have been encouraging and have suggested improved liver function in advanced chronic liver disease and enhanced liver regeneration after portal vein embolization. This article reviews the potential for stem cell therapies to enhance hepatic regeneration in acute and chronic hepatic disease and is based on a MEDLINE and PubMed search for English language articles investigating mechanisms of hepatic regeneration and delivery of cell therapies. Two main mechanisms of potential stem cell therapy delivery have emerged: (1) a direct contribution to the functional hepatocyte population with embryonic, induced pluripotent, or adult stem cells and (2) the promotion of endogenous regenerative processes with bone marrow-derived stem cells. Bioartificial hepatic support systems may be proven to be an effective method of using ex vivo differentiated hepatocytes and be indicated as a bridging therapy to definitive surgery in acute liver failure. The administration of bone marrow-derived stem cells may enhance liver regeneration in chronic liver disease after portal vein embolization and could facilitate regeneration after partial hepatic resection. Ultimately, the most appropriate hepatic disease targets for stem cell therapies will become apparent as mechanisms of stem involvement in hepatic regeneration are further elucidated.
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Stutchfield BM, Rashid S, Forbes SJ, Wigmore SJ. Practical Barriers to Delivering Autologous Bone Marrow Stem Cell Therapy as an Adjunct to Liver Resection. Stem Cells Dev 2010; 19:155-62. [PMID: 19954303 DOI: 10.1089/scd.2009.0412] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Affiliation(s)
- Benjamin M. Stutchfield
- Medical Research Council Centre for Inflammation Research and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Sameena Rashid
- Medical Research Council Centre for Inflammation Research and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Stuart J. Forbes
- Medical Research Council Centre for Inflammation Research and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Stephen J. Wigmore
- Medical Research Council Centre for Inflammation Research and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
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Eckersley-Maslin MA, Warner FJ, Grzelak CA, McCaughan GW, Shackel NA. Bone marrow stem cells and the liver: are they relevant? J Gastroenterol Hepatol 2009; 24:1608-16. [PMID: 19788602 DOI: 10.1111/j.1440-1746.2009.06004.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The contribution of bone marrow stem cell responses to liver homeostasis, injury and malignancy is discussed in this review. Pluripotent stem cells or their more committed progenitor progeny are essential to tissue development, regeneration and repair and are widely implicated in the pathogenesis of malignancy. Stem cell responses to injury are the focus of intense research efforts in the hope of future therapeutic manipulation. Stem cells occur within tissues, such as the liver, or arise from extrahepatic sites, in particular, the bone marrow. As the largest reservoir of stem cells in the adult, the bone marrow has been implicated in the stem cell response associated with liver injury. However, in liver injury, the relative contribution of bone marrow stem cells compared to intrahepatic progenitor responses is poorly characterized. Intrahepatic progenitor responses have been recently reviewed elsewhere. In this review, we have summarized liver-specific extrahepatic stem cell responses originating from the bone marrow. The physiological relevance of bone marrow stem cell responses to adult liver homeostasis, injury and malignancy is discussed with emphasis on mechanisms of bone marrow stem cell recruitment to sites of liver injury and its contribution to intrahepatic malignancy.
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Harb R, Xie G, Lutzko C, Guo Y, Wang X, Hill CK, Kanel GC, DeLeve LD. Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury. Gastroenterology 2009; 137:704-12. [PMID: 19447108 PMCID: PMC2747805 DOI: 10.1053/j.gastro.2009.05.009] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2008] [Revised: 04/15/2009] [Accepted: 05/07/2009] [Indexed: 12/28/2022]
Abstract
BACKGROUND & AIMS Damage to hepatic sinusoidal endothelial cells (SECs) initiates sinusoidal obstruction syndrome (SOS), which is most commonly a consequence of myeloablative chemoirradiation or ingestion of pyrrolizidine alkaloids such as monocrotaline (Mct). This study examines whether SECs are of bone marrow origin, whether bone marrow repair can be a determinant of severity of liver injury, and whether treatment with progenitor cells is beneficial. METHODS Mct-treated female rats received infusion of male whole bone marrow or CD133(+) cells at the peak of sinusoidal injury. The Y chromosome was identified in isolated SECs by fluorescent in situ hybridization. Bone marrow suppression was induced by irradiation of both lower extremities with shielding of the abdomen. RESULTS SECs in uninjured liver have both hematopoietic (CD45, CD33) and endothelial (CD31) markers. After Mct-induced SOS, infusion of bone marrow-derived CD133(+) progenitor cells replaces more than one quarter of SECs. All CD133(+) cells recovered from the SEC fraction after injury are CD45(+). CD133(+)/CD45(+) progenitors also repaired central vein endothelium. Mct suppresses CD133(+)/CD45(+) progenitors in bone marrow by 50% and in the circulation by 97%. Irradiation-induced bone marrow suppression elicited SOS from a subtoxic dose of Mct, whereas infusion of bone marrow during the necrotic phase of SOS nearly eradicates histologic features of SOS. CONCLUSIONS SECs have both hematopoietic and endothelial markers. Bone marrow-derived CD133(+)/CD45(+) progenitors replace SECs and central vein endothelial cells after injury. Toxicity to bone marrow progenitors impairs repair and contributes to the pathogenesis of SOS, whereas timely infusion of bone marrow has therapeutic benefit.
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Affiliation(s)
- Rula Harb
- Division of Gastrointestinal and Liver Diseases and the USC Research Center for Liver Diseases, University of Southern California Keck School of Medicine
| | - Guanhua Xie
- Division of Gastrointestinal and Liver Diseases and the USC Research Center for Liver Diseases, University of Southern California Keck School of Medicine
| | - Carolyn Lutzko
- Department of Pediatrics, University of Southern California Childrens Hospital of Los Angeles
| | - Yumei Guo
- Division of Gastrointestinal and Liver Diseases and the USC Research Center for Liver Diseases, University of Southern California Keck School of Medicine
| | - Xiangdong Wang
- Division of Gastrointestinal and Liver Diseases and the USC Research Center for Liver Diseases, University of Southern California Keck School of Medicine
| | - Colin K. Hill
- Department of Radiation Oncology, University of Southern California Keck School of Medicine
| | - Gary C. Kanel
- Department of Pathology, University of Southern California Keck School of Medicine
| | - Laurie D. DeLeve
- Division of Gastrointestinal and Liver Diseases and the USC Research Center for Liver Diseases, University of Southern California Keck School of Medicine
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Khoo CP, Pozzilli P, Alison MR. Endothelial progenitor cells and their potential therapeutic applications. Regen Med 2009; 3:863-76. [PMID: 18947309 DOI: 10.2217/17460751.3.6.863] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Endothelial progenitor cells (EPCs) are derived from the bone marrow (BM) and peripheral blood (PB), contributing to tissue repair in various pathological conditions via the formation of new blood vessels, that is, neovascularization. EPCs can be mobilized into the circulation in response to growth factors and cytokines released following stimuli such as vascular trauma, wounding and cancer. EPCs are involved in vasculogenesis during embryogenesis, but are now recognized to have a significant bearing upon disease outcome through their contribution to neovascularization in a variety of pathological states in adulthood. EPCs exist in very small numbers, especially in circulating blood in adults where they only account for 0.01% of all cells. We discuss the contribution and potential therapeutic applications of EPCs in disease, also noting the prognostic value of PB EPC numbers, especially in heart disease and cancer.
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Affiliation(s)
- Cheen P Khoo
- ICMS, Centre for Diabetes & Metabolic Medicine (DMM), Barts & The London School of Medicine & Dentistry, Queen Mary University of London, 4 Newark Street, London E12AT, UK.
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Hirschi KK, Ingram DA, Yoder MC. Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2008; 28:1584-95. [PMID: 18669889 DOI: 10.1161/atvbaha.107.155960] [Citation(s) in RCA: 579] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Karen K Hirschi
- Department of Pediatrics, Center for Cell & Gene Therapy and Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
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