Human umbilical cord blood stem cell transplantation for the treatment of chronic spinal cord injury Electrophysiological changes and long-term efficacy

Stem cell transplantation can promote functional restoration following acute spinal cord injury （injury time 〈 3 months）, but the safety and long-term efficacy of this treatment need further exploration. In this study, 25 patients with traumatic spinal cord injury （injury time 〉 6 months） were treated with human umbilical cord blood stem cells via intravenous and intrathecal injection. The follow-up period was 12 months after transplantation. Results found that autonomic nerve functions were restored and the latent period of somatosensory evoked potentials was reduced. There were no severe adverse reactions in patients following stem cell transplantation. These experimental findings suggest that the transplantation of human umbilical cord blood stem cells is a safe and effective treatment for patients with traumatic spinal cord injury

Stem cell transplantation for treatment of cerebral ischemia in rats Effects of human umbilical cord blood stem cells and human neural stem cells

BACKGROUND： Exogenous neural stem cell transplantation promotes neural regeneration. However, various types of stem cells transplantation outcomes remain controversial. OBJECTIVE： To explore distribution, proliferation and differentiation of human neural stem cells （hNSCs） and human umbilical cord blood stem cells （hUCBSCs） following transplantation in ischemic brain tissue of rats, and to compare therapeutic outcomes between hNSCs and hUCBSCs. DESIGN, TIME AND SETTING： Randomized controlled animal studies were performed at the Experimental Animal Center of Nanjing Medical University and Central Laboratory of Second Affiliated Hospital of Nanjing Medical University of China from September 2008 to April 2009. MATERIALS： hNSCs were harvested from brain tissue of 10 13 week old fetuses following spontaneous abortion, and hUCBSCs were collected from umbilical cord blood of full-term newborns at the Second Affiliated Hospital of Nanjing Medical University of China. hNSCs and hUCBSCs were labeled by 5-bromodeoxyuridine （BrdU） prior to transplantation. METHODS： Rat models of cerebral ischemia were established by the suture method. A total of 60 healthy male Sprague Dawley rats aged 7-9 weeks were randomly assigned to hNSC transplantation, hUCBSC transplantation and control groups. The rat models in the hNSC transplantation, hUCBSC transplantation and control groups were infused with hNSC suspension, hUCBSC suspension and saline via the caudal vein, respectively. MAIN OUTCOME MEASURES： The distribution, proliferation and differentiation of hNSCs and hUCBSCs in ischemic brain tissue were observed using immunohistochemical methods. Neurological function in rats was assessed using the neurological severity score. RESULTS： The number of BrdU-positive cells was significantly greater in the hNSC transplantation group compared with hUCBSC transplantation group at 14 days following transplantation （P 〈 0.05） The number of BrdU-positive cells reached a peak at 28 days following transplantation. Nestin-positive, glial fibrillary acidic protein-positive, cyclic nucleotide 3＇ phosphohydrolase-positive and neuron specific enolase-positive cells were visible following transplantation. No significant difference was determined in the constituent ratio of various cells between hNSC and hUCBSC transplantation groups （P 〉 0.05）. The neurological severity score was significantly decreased in rats at 21 days following transplantation （P 〈 0.05）. No significant difference was detected in neurological severity score between hNSC and hUCBSC transplantation groups at various time points （P 〉 0.05）. CONCLUSION： The transplanted hNSCs and hUCBSCs can migrate into ischemic brain tissue, proliferate and differentiate into neuron-like, astrocyte-like and oligodendrocyte-like cells, and improve neurological function in rats with cerebral ischemia.

Risk factors of CMV infection in patients after umbilical cord blood transplantation: a multicenter study in China

Objective： This retrospective study examined risk factors for cytomegalovirus （CMV） infection after umbilical cord blood transplantation （UCBT） and the impact of CMV infection on patient survival. Methods： In all 176 patients, plasma CMV DNA was negative prior to the transplantation, and examined twice a week for 100 d, and then once weekly for additional 300 d. Preemptive antiviral therapy （ganciclovir or foscarnet） was started in patients with 〉 1,000/mL copies of CMV DNA but no full-blown CMV disease, and was discontinued upon two consecutive negative reports of blood CMV DNA test. The survival and risk factors for CMV infection or disease were examined using logistic regression. Results： CMV infection developed in 71% （125/176） of the patients, with a median onset of 32 d. Four patients （2.3%） developed CMV disease. Neither the 5-year overall survival （OS） nor event-free survival （EFS） differed significantly in infected patients vs. those with no infection （59.4% vs. 64.8%, P=0.194; 53.4% vs. 59.1%, P=0.226）. A stepwise multivariate analysis indicated an association of CMV infection with age, high-dose glucocorticoids, the number of transplanted CD34^＋ cells, and the number of platelet transfusion, but not with gender, the conditioning regimen, and the day of neutrophil recovery and chronic graft-versus- host disease （cGVHD）. Conclusions： CMV infection is very common after UCBT, but does not seem to affect long-term survival with preemptive antiviral treatment.

Vein transplantation using human umbilical cord blood stem cells in the treatment of stroke sequela

BACKGROUND: Transplanted mononuclear cell (MNC) of umbilical blood can survive in central nervous system (CNS) of host through blood brain barrier, differentiate into nerve cells, migrate to damaged site and integrate morphological structure and function with nerve cells of host so as to improve deficiencies of sensatory function, motor function and cognitive function and influence on stroke sequela. OBJECTIVE: To observe the vein transplantation of human umbilical cord blood stem cells (HUCBSC) for improving neurological function, limb function and activity of daily living of patients with stroke and evaluate the reliability. DESIGN: Self-controlled study. SETTING: Department of Neurosurgery, the Second People's Hospital of Zhengzhou City; Red-crossed Blood Center of Henan Province; Department of Neurosurgery, the Fist Affiliated Hospital of Zhengzhou University. PARTICIPANTS: A total of 10 patients with stroke sequela were selected from Department of Cerebral Surgery, the Second People's Hospital of Zhengzhou City from April to December 2005. There were 9 males and 1 female aged from 35 to 75 years with the mean age of 56 years. All of them were diagnosed with CT and MRI examination and coincidence with diagnostic criteria of stroke established by the Fourth National Academic Meeting for Cerebrovascular Disease. All patients provided informed consent. METHODS: 80-140 mL umbilical blood of term birth of newborn was selected hermetically and maintained in sterile plastic bag. And then, the blood was centrifugated at the speed of 1 500 r/min for 30 minutes at 22 ℃ in order to separate MNC, i.e., HUCBSC. In addition, after final diagnosis during hospitalization, stroke patients were perfused with HUCBSC through superficial vein of back of the hand. Each patient was averagely perfused with 6 portions of HUCBSC (cellular numbers ≥ 1×108/portion) and the interval between each portion was 1-7 days with the mean interval of 4 days. MAIN OUTCOME MEASURES: ① Neurological function of stroke patients was evaluated with neurological function deficiency (NFD) before treatment and at 3 months after treatment. The scale includes consciousness, level fix function, facial paralysis, language, muscle force of upper limbs, muscle force of lower limb and step function. The total scores ranged from 0 to 45; meanwhile, the lower the scores were, the better the neurological function was. ② Motor function of injured limbs was evaluated with Fugl-Meyer Assessment (FMA), including motor function of upper limbs, motor function of lower limbs, balance ability, sensory function and motion of joint. The total scores ranged from 0 to 226; meanwhile, the higher the scores were, the better the motor function of limbs was. ③ Activities of daily living (ADL) was evaluated with Barthel Index (BI), including having meals, taking a bath, dressing oneself, putting on clothes, walking in balance and stair activity. The total scores ranged from 0 to 100; meanwhile, the higher the scores were, the stronger the ADL was. RESULTS: A total of 10 patients were involved in the final analysis. After treatment, NFD of stroke patients was (10.9±5.09) points, which was lower than that before treatment [(25.4±6.09) points, t =8.213, P < 0.01]. In addition, after treatment, FMA and BI of stroke patients were (80.9±25.00) points and (81.1±15.93) points, respectively, which were higher than those before treatment [(31.9±21.85) points, (36.2±19.41) points, t =13.024, 13.670, P < 0.01]. Immuno-suppressive drugs were not used during the whole therapeutic procedure; moreover, immunological rejection and allergic reaction were not observed during the same period. CONCLUSION: Transplanting HUCBSC through superficial vein of back of the hand is regarded as a simple and safe method for the treatment of stroke sequela.

Child with Wiskott–Aldrich syndrome underwent atypical immune reconstruction after umbilical cord blood transplantation: A case report

BACKGROUND Timely reconstitution of a donor-derived immune system is important for recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation(HSCT).We describe a case of Wiskott–Aldrich syndrome(WAS)treated by umbilical cord blood transplantation(UCBT)with atypical immune reconstruction.CASE SUMMARY A 1-year-old Chinese male infant was diagnosed with WAS.WAS gene sequencing identified the mutation c.777+1G>A(IVS8).On August 8,2017,he was admitted to our hospital for HSCT.We selected an unrelated Human leukocyte antigen 6/10-matched donor for UCBT.After HSCT,the immune reconstitution process was atypical,the lymphocytes reached 0.5×109/L on day 23,and the neutrophils reached 0.5×109/L on day 34.The patient’s recovery throughout the year was good.CONCLUSION An increase in lymphocytes(especially T cells)earlier than granulocytes may be a marker of a good prognosis in UCBT.

Editor's Choice——Umbilical cord blood mesenchymal stem cell differentiation and transplantation in neural regeneration

Previous in vivo experiments have shown that human umbilical cord blood mesenchymal stem cells can promote the proliferation and differentiation of damaged celts, and help to repair damaged sites, Recent studies have reported that umbilical cord blood-derived mesenchymal stem cells can differentiate into neurons and glial cells. Recent studies have reported that the repair mechanisms underlying cord blood stern cells involve the replacement of damaged cells and mediation of the local micro-environment.

Human umbilical cord blood-derived mononuclear cell transplantation for umbilical hernia and hepatic hydrothorax in primary biliary cirrhosis

Cell therapy was proposed as a potential treatment intervention for liver cirrhosis recently due to the fact that the therapeutic protocol for primary biliary cirrhosis (PBC)-associated refractory umbilical hernia and hepatic hydrothorax is not well defined currently. We report herein the case of a 58-year-old woman who received routine treatments for PBC, which developed into an incarcerated hernia and uncontrolled hydrothorax. This subject’s condition was significantly improved and maintained stable condition after receiving human umbilical cord blood-derived mononuclear cell (CBMC) transplantation. Consequently, this new strategy may be a potential treatment option for the refractory umbilical hernia and hydrothorax caused by PBC. However, sufficient data from large-scale controlled and double-blinded clinical trials are needed to further confirm the treatment efficacy and longterm safety before this cell transplantation can be used as a regular therapy for liver cirrhosis.

Experimental study on human umbilical cord blood scheduled transplanta-tion in severe combined immunodeficient mice

Objective: To explore a new way for developing the human umbilical cord blood (CB) engraftment with high efficiency and in further understand the homing potentiality of hematopoietic stein/progenitor cells (HSC/HPC). Method: Sub-lethally irradiated severe combined immunodeficient (SCID) mice were transplanted i. v. with CB which was cryopre- served at - 80℃. Human cells in recipient mice were detected by flow cytometry and CFU-GM assay for each host organ. Results: In contrast with the single transplantation, scheduled engraftment of the identical numbers of CB cells resulted in an obvious increase of CD45+ and CD34+ cells produced in SCID mouse bone marrow (BM). While the donor cells were reduced by 5 times, the similar reconstitution of both hematopoietic fumctions and part of immunologic fumctions was ob- tained.Conclusion:Scheduled engraftment can improve repopulating of the HSC, which provides a novel way for clinical cord blood engraftment into adults.

Differentiation of human umbilical cord blood stem cells into hepatocytes in vivo and in vitro

瞄准：学习人的脐带血干细胞(HUCBSC ) 的条件和潜力区分进 hepatocytes 在活体内或在试管内。方法：在人的脐带血的房间文化研究干细胞(HUCBSC ) 区别，人的脐带血单音的原子房间(HUCBMNC ) 被密度坡度远心沉淀分开。成纤维细胞生长因素(FGF ) 和 hepatocyte 生长因素(HGF ) 和胎儿的肝的上层清液在劝诱的组被增加。仅仅 FGF 在控制组被增加。在每个组的 HUCBMNC 的扩大和区别被观察。人的高山哈 fetoprotein (法新社) 和白朊(白长袍的) 被免疫组织化学检测。在动物实验，有在四氯化碳(CCL4 ) 以后的尖锐肝的损害的幸存 SD 老鼠注射 48 h 随机被划分成三个组。在组 A 的老鼠与人的脐带血浆液被对待。在组 B 的老鼠与 HUCBMNC 移植被对待。在组 C 的老鼠与移植为 7 d 由腹膜内出租机动三轮车磷酰胺跟随了的 HUCBMNC 被对待。在处理和肝织物是免疫组织化学检测的学习的组织病理学说的联盟者和人的法新社和白长袍的以后，老鼠在不同时间点被打死。在肝织物的人的 X 不活跃特定的抄本基因碎片被 PCR 放大发现人的 DNA。结果：房间文化的结果证明支持者房间在控制组是为法新社或白长袍的染色的 negative。然而，在劝诱的组的支持者房间染色了为法新社或白长袍的积极。动物实验的结果显示出那个不人的法新社或在组 A (控制组) 的肝织物在场的白长袍的积极细胞。然而，许多人的法新社或白长袍的积极房间在湾穴附近被散布肝我们和肝的腹片并且在在在一个月以后的组 B 和组 C 的门区域的中央静脉。人的 X 浓度基因的碎片能在组 B 和 C 的肝织物，然而并非在组 A 被检测。结论：在进肝细胞在活体内和在试管内的某些条件 HUCBSC 罐头 differentiate 下面。

Haploidentical vs cord blood transplantation for adults with acute myelogenous leukemia

Hematopoeitic cell transplantation is established as a curative treatment for patients w acute myelogenous leukemia. Haploidentical family donor and umbilical cord blood(UCB) are alternative sources of stem cells for patients lacking a matched sibling or unrelated do-nor. The early challenges of transplant complications related to poor engraftment and graft-vs-host disease have been overcome with new strategies such as using 2 units and increased cell dose in UCB and T-cell deple-tion and post transplantation cyclophosphamide in hap-loidentical transplantation. The outcomes of alternative transplantation for acute leukemia were compared to other traditional graft sources. For patients lacking a matched sibling or unrelated donor, either strategy is a suitable option. The choice should rely mostly on the urgency of the transplantation and the available cell dose as well as the expertise available at the trans-plant center. This manuscript reviews the options of alternative donor transplantation and highlights recent advances in each of these promising transplantation options.

Stem cell transplantation for spinal cord injury： a meta-analysis of treatment effectiveness and safety

OBJECTIVE： The aim of this study was to evaluate the effectiveness and safety of stem cell transplantation for spinal cord injury（SCI）.DATA SOURCES： PubM ed, EMBASE, Cochrane, China National Knowledge Infrastructure, China Science and Technology Journal, Wanfang, and Sino Med databases were systematically searched by computer to select clinical randomized controlled trials using stem cell transplantation to treat SCI, published between each database initiation and July 2016. DATA SELECTION： Randomized controlled trials comparing stem cell transplantation with rehabilitation treatment for patients with SCI. Inclusion criteria：（1） Patients with SCI diagnosed according to the American Spinal Injury Association（ASIA） International standards for neurological classification of SCI;（2） patients with SCI who received only stem cell transplantation therapy or stem cell transplantation combined with rehabilitation therapy;（3） one or more of the following outcomes reported： outcomes concerning neurological function including sensory function and locomotor function, activities of daily living, urination functions, and severity of SCI or adverse effects. Studies comprising patients with complications, without full-text, and preclinical animal models were excluded. Quality of the included studies was evaluated using the Cochrane risk of bias assessment tool and Rev Man V5.3 software, provided by the Cochrane Collaboration, was used to perform statistical analysis. OUTCOME MEASURES： ASIA motor score, ASIA light touch score, ASIA pinprick score, ASIA impairment scale grading improvement rate, activities of daily living score, residual urine volume, and adverse events.RESULTS： Ten studies comprising 377 patients were included in the analysis and the overall risk of bias was relatively low level. Four studies did not detail how random sequences were generated, two studies did not clearly state the blinding outcome assessment, two studies lacked blinding outcome assessment, one study lacked follow-up information, and four studies carried out selective reporting. Compared with rehabilitation therapy, stem cell transplantation significantly increased the lower limb light touch score（odds ratio（OR） = 3.43, 95% confidence interval（CI）： 0.01 – 6.86, P = 0.05）, lower limb pinprick score（OR = 3.93, 95%CI： 0.74 – 7.12, P = 0.02）, ASI grading rate（relative risk（RR） = 2.95, 95%CI： 1.64 – 5.29, P = 0.0003）, and notably reduced residual urine volume（OR = –8.10, 95%CI： –15.09 to –1.10, P = 0.02）. However, stem cell transplantation did not significantly improve motor score（OR = 1.89, 95%CI： –0.25 to 4.03, P = 0.08） or activities of daily living score（OR = 1.12, 95%CI： –1.17 to 4.04, P = 0.45）. Furthermore, stem cell transplantation caused a high rate of mild adverse effects（RR = 14.49, 95%CI： 5.34 – 34.08, P 〈 0.00001）; however, these were alleviated in a short time. CONCLUSION： Stem cell transplantation was determined to be an efficient and safe treatment for SCI and simultaneously improved sensory and bladder functions. Although associated minor and temporary adverse effects were observed with transplanted stem cells, spinal cord repair and axon remyelination were apparent. More randomized controlled trials with larger sample sizes and longer follow-up times are needed to further validate the effectiveness of stem cell transplantation in the treatment of SCI.

Combined use of Y-tube conduits with human umbilical cord stem cells for repairing nerve bifurcation defects

Given the anatomic complexity at the bifurcation point of a nerve trunk,enforced suturing between stumps can lead to misdirection of nerve axons,thereby resulting in adverse consequences.We assumed that Y-tube conduits injected with human umbilical cord stem cells could be an effective method to solve such problems,but studies focused on the best type of Y-tube conduit remain controversial.Therefore,the present study evaluated the applicability and efficacy of various types of Y-tube conduits containing human umbilical cord stem cells for treating rat femoral nerve defects on their bifurcation points.At 12 weeks after the bridging surgery that included treatment with different types of Y-tube conduits,there were no differences in quadriceps femoris muscle weight or femoral nerve ultrastructure.However,the Y-tube conduit group with longer branches and a short trunk resulted in a better outcome according to retrograde labeling and electrophysiological analysis.It can be concluded from the study that repairing a mixed nerve defect at its bifurcation point with Y-tube conduits,in particular those with long branches and a short trunk,is effective and results in good outcomes.

Reconstitution of double-negative T cells after cord blood transplantation and its predictive value for acute graft-versus-host disease

Background:With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation(UCBT),the correlation between immune reconstitution(IR)after UCBT and graft-versus-host disease(GVHD)has been reported successively,but reports on double-negative T(DNT)cell reconstitution and its association with acute GVHD(aGVHD)after UCBT are lacking.Methods:A population-based observational study was conducted among 131 patients with hematological malignancies who underwent single-unit UCBT as their first transplant at the Department of Hematology,the First Affiliated Hospital of USTC,between August 2018 and June 2021.IR differences were compared between the patients with and without aGVHD.Results:The absolute number of DNT cells in the healthy Chinese population was 109(70-157)/μL,accounting for 5.82(3.98-8.19)%of lymphocytes.DNT cells showed delayed recovery and could not reach their normal levels even one year after transplantation.Importantly,the absolute number and percentage of DNT cells were significantly higher in UCBT patients without aGVHD than in those with aGVHD within one year(F=4.684,P=0.039 and F=5.583,P=0.026,respectively).In addition,the number of DNT cells in the first month after transplantation decreased significantly with the degree of aGVHD increased,and faster DNT cell reconstitution in the first month after UCBT was an independent protective factor for aGVHD(HR=0.46,95%confidence interval[CI]:0.23-0.93;P=0.031).Conclusions:Compared to the number of DNT cells in Chinese healthy people,the reconstitution of DNT cells in adults with hematological malignancies after UCBT was slow.In addition,the faster reconstitution of DNT cells in the early stage after transplantation was associated with a lower incidence of aGVHD.

Stem cell transplantation for treating spinal cord injury A literature comparison between studies of stem cells obtained from various sources

OBJECTIVE： To identify global research trends of stem cell transplantation for treating spinal cord injury using a bibliometric analysis of the Web of Science. DATA RETRIEVAL： We performed a bibliometric analysis of data retrievals for stem cell transplantation for treating spinal cord injury from 2002 to 2011 using the Web of Science. SELECTION CRITERIA： Inclusion criteria： （a） peer-reviewed articles on stem cell transplantation for treating spinal cord injury that were published and indexed in the Web of Science; （b） type of articles： original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material, and news items; and （c） year of publication： 2002-2011. Exclusion criteria： （a） articles that required manual searching or telephone access; （b） documents that were not published in the public domain; and （c） a number of corrected papers from the total number of articles. MAIN OUTCOME MEASURES： （1） Annual publication output; （2） distribution according to country; （3） distribution according to institution; （4） distribution according to journals; （5） distribution according to funding agencies; and （6） top cited articles over the last 10 years. RESULTS： Bone marrow mesenchymal stem cells and embryonic stem cells have been widely used for treating spinal cord injury. In total, 191 studies of bone marrow mesenchymal stem cell transplantation and 236 studies of embryonic stem cell transplantation for treating spinal cord injury appeared in the Web of Science from 2002 to 2011, and almost half of which were derived from American or Japanese authors and institutes. The number of studies of stem cell transplantation for treating spinal cord injury has gradually increased over the past 10 years. Most papers on stem cell transplantation for treating spinal cord injury appeared in journals with a particular focus on stem cell research, such as Stem Cells and Cell Transplantation. Although umbilical cord blood stem cells and adipose-derived stem cells have been studied for treating spinal cord injury, the number of published papers was much smaller, with only 21 and 17 records, respectively, in the Web of Science. CONCLUSION： Based on our analysis of the literature and research trends, we found that stem cells transplantation obtained from various sources have been studied for treating spinal cord injury; however, it is difficult for researchers to reach a consensus on this theme.

WJSC 6^(th) Anniversary Special Issues(1):Hematopoietic stem cell transplantation Allogeneic hematopoietic cell transplant for acute myeloid leukemia:Current state in 2013 and future directions

Acute myeloid leukemia(AML)represents a heterogeneous group of high-grade myeloid neoplasms of the elderly with variable outcomes.Though remissioninduction is an important first step in the management of AML,additional treatment strategies are essential to ensure long-term disease-free survival.Recent pivotal advances in understanding the genetics and molecular biology of AML have allowed for a risk-adapted approach in its management based on relapse-risk.Allogeneic hematopoietic cell transplantation(allo-HCT)represents an effective therapeutic strategy in AML providing the possibility of cure with potent graft-versus-leukemia reactions,with a demonstrable survival advantage in younger patients with intermediate-or poor-risk cytogenetics.Herein we review the published data regarding the role of allo-HCT in adults with AML.We searched MEDLINE/PubMed and EMBASE/Ovid.In addition,we searched reference lists of relevant articles,conference proceedings and ongoing trial databases.We discuss the role of allo-HCT in AML patients stratified by cytogenetic-and molecular-risk in first complete remission,as well as allo-HCT as an option in relapsed/refractory AML.Besides the conventional sibling and unrelated donor allografts,we review the available data and recent advances for alternative donor sources such as haploidentical grafts and umbilical cord blood.We also discuss conditioning regimens,including reduced intensity conditioning which has broadened the applicability of allo-HCT.Finally we explore recent advances and future possibilities and directions of allo-HCT in AML.Practical therapeutic recommendations have been made where possible based on available data and expert opinion.

Stem cell transplantation for treating stroke:status,trends and development

The developing approaches of thrombolytic therapy, endovascular treatment, neuroprotective therapy, and stem cell therapy have enabled breakthroughs in stroke treatment. In this study, we summarize and analyze trends and progress in stem cell transplantation for stroke treatment by retrieval of literature from Thomson Reuters Web of Science database, the NIH Clinical Trial Planning Grant Program, and Clinical Trials Registration Center in North America. In the last 10 years, there has been an increasing number of published articles on stem cell transplantation for stroke treatment. In particular, research from the USA and China has focused on stem cell transplantation. A total of 2,167 articles addressing stem cell transplantation for stroke treatment from 2004 to 2013 were retrieved from the Thomson Reuters Web of Science database. The ma- jority of these articles were from the USA （854, 39.4%）, with the journal Stroke publishing the most articles （145, 6.7%）. Of the published articles, 143 were funded by the National Institutes of Health （accounting for 6.6% of total publications）, and 91 by the National Natural Science Foundation of China. Between 2013 and 2014, the National Institutes of Health provided finan- cial support （$130 million subsidy） for 329 research projects on stroke therapy using stem cell transplantation. In 2014, 215 new projects were approved, receiving grants of up to $70,440,000. Ninety clinical trials focusing on stem cell transplantation for stroke were registered in the Clinical Trial Registration Center in North America, with 40 trials registered in the USA （ranked first place）. China had the maximum number of registered research or clinical trials （10 projects）.

Optimal time for human umbilical cord blood cell transplantation in rats with myocardial infarction

Background Cell therapy for cardiac regeneration is still under investigation. To date there have been a limited number of studies describing the optimal time for cell injection. The present study aimed to examine the optimal time for human umbilical cord blood cells （HUCBCs） transplantation after myocardial infarction （MI）. Methods The animals underwent MI by ligation of the left anterior descending coronary artery and received an intravenous injection of equal volumes of HUCBCs or phosphate buffered saline at days 1, 5, 10 and 30 after MI. HUCBCs were detected by immunostaining against human human leucocyte antigen （HLA）. Cardiac function, histological analysis and measurement of vascular endothelial growth factor （VEGF） were performed 4 weeks after cell transplantation. Results HUCBCs transplantation could improve cardiac function in rats that received transplantation at 5 and 10 days after MI. The best benefit was achieved in rats that received cells at 10-day after MI. Survival of engrafted HUCBCs, angiogenesis and VEGF expression were more obvious in the 10-day transplantation group than in the other transplantation groups. No evidence of cardiomyocyte regeneration was detected in any transplanted rats. Conclusions HUCBCs transplantation could improve cardiac function in rats that received HUCBCs at days 5 and 10 after MI with the optimal time for transplantation being 10 days post MI. Angiogenesis, but not cardiomyocyte regeneration, played a key role in the cardiac function improvement.

Long-term outcomes in adults with leukemia treated with transplantation of two unrelated umbilical cord blood units

Background Wide application of umbilical cord blood transplantation （UCBT） in adult patients is limited by low cell-dose available in one umbilical cord blood （UCB） unit. The aim of this study was to investigate the safety and long-term outcomes of UCBT from unrelated donors in adult and adolescent patients with leukemia. Methods Thirteen patients with leukemia received double-unit UCBT with human leukocyte antigen （HLA） mismatched at 0-2 loci. We analyzed the engraftment, graft-versus-host disease （GVHD） and survival. Results Twelve evaluable patients （92.3%） had neutrophil and platelet engraftment at a median of 21 days （range, 16-38 days） and 34 days （range, 25-51 days）, respectively. At day 30, engraftment was derived from one donor in 8 patients （66.7%, 95% Cl 40.0%-93.4%）, and from both donors in 4 patients （33.3%, 95% CI 6.7%-60.0%） with 1 unit predominated. Unit with larger nucleated cell （NC） dose would predominate in engraftment （P=-0.039）, whereas CD34~ cell dose or HLA-match failed to demonstrate any relationship with unit predominance. Only one patient developed grade II acute graft-versus-host disease （aGVHD）. Chronic GVHD （cGVHD） was observed in 2 of 11 patients who survived more than 100 days, and both were limited. The median follow-up after transplantation for the 13 patients was 45 months （range 1.5-121.0 months） and 72 months （range 41.0-121.0 months） for the 8 alive and with full donor chimerism. The 5-year cumulative disease free survival （DFS） was （61.5±13.5）%. Of the 13 patients, 5 patients died in 1 year and 1-year transplantation related mortality （TRM） was 23.1% （95% Cl 0.2%-46.0%）. Conclusion Double-unit UCBT from unrelated donors with HLA-mismatched at 0-2 loci may overcome the cell-dose barrier and be feasible for adults and adolescents with leukemia.

Transplanted human umbilical cord blood mononuclear cells improve left ventricular function through angiogenesis in myocardial infarction

Background Human umbilical cord blood contains an abundance of immature stem/progenitor cells, which may participate in the repair of hearts that have been damaged by myocardial infarction （MI）. This study aimed to evaluate the effects of human umbilical cord blood mononuclear cells （hUCBC） transplantation on cardiac function and left ventricular remodeling in rat model of MI. Methods Forty-five male Wistar rats were randomized into three groups： MI or control group （n=15）, MI plus cell transplantation （n=15）, and sham group （n=15）. Acute myocardial infarction （AMI） was established by ligating the left anterior descending artery, thereafter, hUCBC were implanted into the marginal area of infarcted myocardium. In MI/control group, DMEM was injected instead of hUCBC following the same protocol. Left ventricular function assessment was carded out by echocardiography and invasive hemodynamic measurements one month post MI. All rats were sacrificed for histological and immunochemical examinations.Results The transplanted hUCBC survived and engaged in the process of myocardial repair in the host heart. Echocardiography demonstrated that left ventricular function improved significantly in the rats that underwent cell transplantation. Hemodynamic studies found a significantly decreased left ventricular end-diastolic pressure （LVEDP） [（21.08±8.10） mmHg vs （30.82±9.59） mmHg, P〈0.05], increase in ＋dp/dtmax [（4.29± 1.27） mmHg/ms vs （3.24±0.75） mmHg/ms, P〈0.05）, and increase in -dp/dtmax [（3.71 ±0.79） mmHg/ms vs （3.00± 0.49） mmHg/ms, P〈0.05] among MI group with hUCBC transplantation when compared with MI/control group. Masson＇s trichrome staining revealed that the collagen density in the left ventricle was significantly lower in rats of transplantation group than that in the MI control groups [（6.33±2.69）% vs （11.10±3.75）%, P〈 0.01]. Based on immunostaining of α-actin, the numbers of microvessels were significantly （P〈0.01） increased at the boundary of infarction site. Similarly higher mRNA expression of vascular endothelial growth factor （VEGF） 164 and VEGF188 were found at 7- and 28-day post cell transplantation in MI group with hUCBC transplantation when compared with MI/control group. Conclusions Transplanted hUCBC can survive in host myocardium without immunorejection, significantly improve left ventricular remodeling after AMI and promote a higher level of angiogenesis in the infarct zones. All these factors beneficially affect cardiac repair in the setting of MI. Therefore human umbilical cord blood may be potential source for cell-based therapy for AMI.

Transplantation of human umbilical cord-derived endothelial progenitor cells promotes re-endothelialization of the injured carotid artery after balloon injury in New Zealand white rabbits

Background Cell transplantation has great potential for promoting endothelial repair and reducing the complications of percutaneous coronary intervention （PCI）. The aim of this study was to investigate the effect of transplantation of human umbilical cord blood endothelial progenitor ceils （EPCs） on injured arteries. Methods Umbilical cord blood mononuclear cells were obtained from post-partum lying-in women, and EPCs were isolated, cultured, expanded and identified by immunofiuorescence. The carotid arterial endothelium of New Zealand white rabbits was injured by dilatation with a 3F balloon, and the EPCs were injected into the lumen of the injured artery in the transplanted group （n=16）, while an equal volume of phosphated buffered saline （PBS） was injected into the control group after balloon injury （n=16）. The animals were sacrificed after either 2 or 4 weeks, and the grafted cells were identified by double immunofluorescence staining with human nuclear antigen （HNA） and CD31 antibodies. Arterial cross sections were analyzed by pathology, immunohistochemisty and morphometry to evaluate the reparative effects of EPCs. Proliferating cell nuclear antigen （PCNA） and transforming growth factor （TGF）-131 mRNA expression were detected by reverse transcription-polymerase chain reaction （RT-PCR）. Results Fluorescence-labeled EPCs were found in the neointima. The neointimal area and the neointimal/medial area ratio were significantly lower in the transplanted group than in the control group （P 〈0.05）. von Willebrand factor （vWF） immunohistostaining showed more VWF-positive cells in the transplanted animals than in the controls （8.75±2.92 vs. 4.50±1.77, P 〈0.05）. Compared with the control group, the transplanted group had lower expression of PCNA mRNA （0.67±0.11 vs. 1.25±0.40, P 〈0.01 ）and higher expression of TGF-β1 mRNA （1.10±0.21 vs. 0.82±0.07, P 〈0.05）. Conclusions EPCs derived from human umbilical cord blood were successfully transplanted into injured vessels. The transplanted EPCs inhibited neointimal hyperplasia and promoted vascular re-endothelialization.