Cell Grafts Research Articles

Peripheral blood stem cell versus bone marrow graft for patients ≥60 years undergoing reduced intensity conditioning haploidentical transplantation for acute myeloid leukemia in complete remission: An analysis of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

In the context of T-cell replete haploidentical stem cell transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy), it is still unknown whether peripheral blood (PB) or bone marrow (BM) is the best graft source. While PB is associated with a higher incidence of graft-versus-host disease (GVHD), it may induce a stronger graft-versus-leukemia effect compared to BM, notably in acute myeloid leukemia (AML). From the EBMT registry database, we compared T-cell replete PB (n = 595) versus BM (n = 209) grafts in a large cohort of 804 patients over the age of 60 years who underwent Haplo-SCT with PT-Cy for an AML in first or second complete remission. The risk of acute GVHD was significantly higher in the PB group (Grade II-IV: HR = 1.67, 95% CI [1.10-2.54], p = 0.01; Grade III-IV: HR = 2.29, 95% CI [1.16-4.54], p = 0.02). No significant difference was observed in chronic GVHD or non-relapse mortality. In the PB group, the risk of relapse was significantly lower in the PB group (HR = 0.65, 95% CI [0.45-0.94], p = 0.02) and leukemia-free survival was significantly better (HR = 0.76, 95% CI [0.59-0.99], p = 0.04), with a trend toward better overall survival (HR = 0.78, 95% CI [0.60-1.01], p = 0.06). We conclude that in the specific context of Haplo-SCT with PT-Cy, PB grafts represent a valid option to decrease the risk of relapse and improve outcome of older AML patients who usually do not benefit from conditioning intensification.

Hybrid cord blood banking in a private-public-partnership: Women's perspectives.

The increasing demand for umbilical cord blood (UCB) used in stem cell transplantation led to the establishment of cord blood (CB) banks worldwide. These include public foreign donor banks and private family-directed donor banks. Recently, our department has introduced a third banking model within a private-public-partnership. This hybrid banking allows for storage of family-directed CB units, while also getting Human leukocyte antigen (HLA)-typed and included in the national stem cell donor registry. So if the need arises, the HLA-compatible CB unit can be released to an unrelated recipient as a foreign donor stem cell graft. The aim of this study was to evaluate women's perspectives on the different CB banking options as well as retrospective satisfaction with their decisions. We performed a prospective survey study in postpartum women, using a validated questionnaire. A total of 157 women were included in this survey study; 68% of them decided to have their UCB stored or donated. Among those women, 25% of them opted for hybrid storage, 72% of respondents stored UCB publicly, and 3% decided for private family-directed storage. Our study shows the potential of hybrid banking as an attractive UCB storage option, as an alternative to family-directed banking rather than a substitute for public donation. Hybrid storage potentially combines advantages of family-directed banking as well as unrelated CB donation expanding the number of registered CB units available for transplantation and giving every pregnant woman the possibility to store UCB.

Noncultured Trypsinized Epidermal Cell Suspension Transplantation After Cryoblebbling Versus Noncultured Nontrypsinized Epidermal Cell Graft Homogenized With Plasma Gel After Dermabrasion for Stable Vitiligo.

Vitiligo treatment is challenging, especially for resistant and stable vitiligo, which requires surgical management. Noncultured epidermal cell suspension has been modified to enhance the treatment outcomes. Comparison of autologous noncultured trypsinized epidermal cell suspension in recipient site prepared by cryoblebbling and noncultured nontrypsinized epidermal cell graft homogenized with plasma gel in recipient site prepared by dermabrasion for stable vitiligo treatment. Interventional comparative study on 30 patients with stable vitiligo, randomly divided into 2 equal groups. Group A: noncultured trypsinized epidermal cell suspension for recipient prepared by cryoblebbling. Group B: noncultured nontrypsinized epidermal cell graft homogenized with plasma gel for recipient prepared by dermabrasion. Afterward, both groups received 3 months of narrow-band ultraviolet B phototherapy. The plasma gel group showed a significantly earlier onset of repigmentation and faster healing ( p = .002* and <.001*, respectively). Overall, repigmentation was higher in the plasma gel group ( p = .037* at the end of the second month). Color matching and patient satisfaction were higher in the plasma gel group, without statistical significance. The cryobleb group showed more recipient site complications, and the plasma gel procedure was relatively easier and cheaper. Plasma gel modification is cost-effective, less time-consuming, does not require trypsinization, and provides rapid, satisfactory, and uniform repigmentation. Cryoblebbing and trypsinization are effective; however, there are more technical difficulties, delayed healing, and delayed onset of repigmentation.

Treatment-Responsive Acute Graft-versus-Host Disease after Post-Transplantation Cyclophosphamide-Based Prophylaxis: Incidence and Clinical Outcomes

Post-transplantation cyclophosphamide (PTCy) following hematopoietic cell transplantation (HCT) has emerged as standard of care for graft-versus-host disease (GVHD) prevention in adult patients without increasing malignant relapse. We previously defined acute GVHD (aGVHD) treatment response categories as corticosteroid-sensitive (SS), -dependent (SD), or -resistant (SR) based on response to first-line corticosteroids and reported their clinical outcomes following non-PTCy-based prophylaxis. More than one-third of patients developed aGVHD necessitating systemic therapy. Cases were predominantly SR, with a 14% overall incidence of SR aGVHD. The incidence and clinical outcomes of these 3 distinct aGVHD treatment response groups following PTCy-based prophylaxis have not been well described. The objective of this retrospective single-institution cohort study was to assess the incidence and clinical outcomes of SS, SD, and SR aGVHD following HCT with PTCy-based prophylaxis using a prophylactic regimen of PTCy, tacrolimus, and mycophenolate mofetil (MMF). We included 196 consecutive adult and pediatric patients undergoing allogeneic HCT for malignant and non-malignant disorders at the University of Minnesota between 2017 and 2021. Patients received PTCy on days +3 and +4 plus tacrolimus and MMF prophylaxis. Bone marrow and peripheral blood stem cell graft sources and related and unrelated donors were included. Recipients received myeloablative or reduced-intensity conditioning regimens. Of the 196 allografts, 54 (28%) developed aGVHD before day +180, with a median time to onset of 50 days (interquartile range, 34 to 71 days). Of those, 32 patients (16% overall) developed maximum grade II-III aGVHD necessitating systemic corticosteroids, with the following response: 13 SS (41%), 10 SD (31%), and 9 SR (28%). The overall incidence of SR aGVHD was 4.6%. Only 12 patients (6%) developed maximum grade III aGVHD, and none had grade IV aGVHD. The 2-year overall survival analyzed from 80 days after initiation of systemic treatment was similar in the SS and SD groups (77 and 75%, respectively), comparable to those without aGVHD (81%), and was lowest in the SR group (20%), with GVHD the primary cause of death. Nonrelapse mortality was highest in the SR group. MN high-risk and higher GVHD grade at onset were risk factors for developing SR aGVHD. Overall, we report a low incidence (16%) of aGVHD requiring systemic corticosteroids with PTCy-based prophylaxis. aGVHD cases were predominantly SS aGVHD, with lower incidences of SD and SR aGVHD. Our findings suggest that PTCy-based prophylaxis reduces the rate of treatment-resistant aGVHD. Patients with SR aGVHD had the worst clinical outcomes and poorest survival. Those with SS and SD aGVHD had similar clinical outcomes, both better than seen with SR aGVHD.

LA GREFFE DES CELLULES ADIPEUSES DANS LESTHETIQUE DE LA FACE: TECHNIQUE ET INDICATIONS

The objective of our study is to highlight the technique, the different indications, and the results of autologous fat grafting in facial aesthetics by reporting the experience of our department and through a literature review. This is a retrospective study involving 14 patients who underwent aesthetic and reparative facial fat grafting over a period of 2 years, from January 1, 2022, to January 1, 2024, at the Department of Plastic, Reconstructive, Aesthetic, and Burn Surgery of the Mohammed VI University Hospital Center in Marrakech. We collected 22 autologous facial fat grafts, with the mean age of our patients being 26.36 years, ranging from 11 to 58 years. A clear female predominance was noted (86.4%) with a female-to-male ratio of 6. The two main indications were atrophy and volume enhancement (72%) and contour refinement (28%). The procedures were performed under general anesthesia. The fat was harvested from a single donor site: the abdominal region. The mean volume harvested was 96.8 ml, ranging from 80 ml to 120 ml. All samples were centrifuged at a speed of 3,000 rpm for 3 minutes. The mean injected volume was 25.55 ml, ranging from 5 to 90 ml. 10% of the fat grafts were associated with a facelift. The average length of hospital stay was 1 day. None of our patients experienced immediate or late complications. 68% of patients underwent a single fat grafting session, 21% underwent 2 sessions, and only 11% required 3 sessions. The mean interval between sessions was 3 months. Subjective evaluation of satisfaction 3 months after the last intervention revealed a satisfaction rate of 90%. Adipose cell grafting is currently considered an ideal method for facial rejuvenation and reshaping due to its safety, simplicity, reproducibility, and the durable and natural results it achieves.

Molecular mechanisms of Asparagus racemosus willd. and Withania somnifera (L.) Dunal as chemotherapeutic adjuvants for breast cancer treatment

Ethnopharmacological relevanceDespite various treatment modalities, the progression and metastasis of breast cancer (BC) are grave concerns due to the alarming disease-free survival rate (DFS) and overall survival rate (OS) of affected patients. Over the years, many antibiotics, synthetic compounds, medicinal plant isolates and polyherbal combinations have been used as adjuvants in therapy for the management of primary and secondary tumors. Paclitaxel (PTX)-based chemotherapy for breast cancer causes multiple adverse side effects in patients. Withania somnifera (L.) Dunal (WS) and Asparagus racemosus Willd. (AR) as Ayurveda-inspired plant-based adjuvants were investigated for their anticancer effects on MDA-MB-231 and 4T1 cells in mouse model systems. Aim of the studyThis study focused on evaluating the adjuvant properties of WS and AR plant extracts with PTX and their effectiveness over PTX alone in terms of tumor inhibition. Materials and methodsThe effects of WS and AR on DNA double-strand breaks (DSBs), senescence induction and mitochondrial functions were evaluated in BC cells in vitro. The potential for cancer stem cell (CSC) inhibition was evaluated via mammosphere formation assays and CD44/CD24 immunostaining. In vivo tumor growth studies were conducted in athymic BALB/c mice for MDA-MB-231 cells and in BALB/c mice for 4T1 cells. ResultsInduction of senescence was evident due to DSBs induced by the WS and AR extracts. Mammosphere formation and CD44/CD24 CSC markers were reduced after treatment with WS, AR or the combination of both in MCF-7 cells. WS or AR inhibited epithelial-to-mesenchymal transition (EMT). In vivo studies demonstrated that tumor growth inhibition was more pronounced in the treated group than in the PTX alone group and the untreated control group. ConclusionOur study showed that the use of WS or AR plant hydroalcoholic extracts in combination with paclitaxel (PTX) has better effects on sensitivity and efficacy than PTX alone, as demonstrated in in vitro BC cells and mouse models with BC cell grafts. Hence, scheduling adjuvant therapy with WS or AR alone or combined with PTX can be advantageous for the management of triple-negative BC (TNBC). Further studies are warranted in human clinical conditions to ascertain the efficacy of these treatments.

Dopaminergic Cell Replacement for Parkinson's Disease: Addressing the Intracranial Delivery Hurdle.

Parkinson's disease (PD) is an increasingly prevalent neurological disorder, affecting more than 8.5 million individuals worldwide. α-Synucleinopathy in PD is considered to cause dopaminergic neuronal loss in the substantia nigra, resulting in characteristic motor dysfunction that is the target for current medical and surgical therapies. Standard treatment for PD has remained unchanged for several decades and does not alter disease progression. Furthermore, symptomatic therapies for PD are limited by issues surrounding long-term efficacy and side effects. Cell replacement therapy (CRT) presents an alternative approach that has the potential to restore striatal dopaminergic input and ameliorate debilitating motor symptoms in PD. Despite promising pre-clinical data, CRT has demonstrated mixed success clinically. Recent advances in graft biology have renewed interest in the field, resulting in several worldwide ongoing clinical trials. However, factors surrounding the effective neurosurgical delivery of cell grafts have remained under-studied, despite their significant potential to influence therapeutic outcomes. Here, we focus on the key neurosurgical factors to consider for the clinical translation of CRT. We review the instruments that have been used for cell graft delivery, highlighting current features and limitations, while discussing how future devices could address these challenges. Finally, we review other novel developments that may enhance graft accessibility, delivery, and efficacy. Challenges surrounding neurosurgical delivery may critically contribute to the success of CRT, so it is crucial that we address these issues to ensure that CRT does not falter at the final hurdle.

Eltrombopag can promote platelet implantation after allogeneic hematopoietic stem cell transplantation as safely and similarly to thrombopoietin.

Eltrombopag has demonstrated efficacy in treating low platelet (PLT) levels, but it remains unclear whether eltrombopag can promote PLT engraftment after hematopoietic stem cell transplantation (HSCT). Forty-one HSCT patients received eltrombopag 50 mg/d from +1 day until PLT >50 × 109/L or 1 month after HSCT. Fifty-one patients in the same period received thrombopoietin (TPO) to promote PLT graft after HSCT and served as a control group. A total of 51 patients who applied TPO during the same period were treated as a control. In the eltrombopag group, the median time to white blood cells (WBC) graft was 12 days (range, 10-17 days) and the PLT graft was 15 days (range, 10-30 days), whereas for the patients in the TPO group, the median time to WBC and PLT graft was 12 days (range, 9-23 days) and 15.5 days (range, 9-41 days), respectively. In the first month after HSCT, the median WBC count in the eltrombopag group was 4.41 × 109/L (range, 0.87-40.01 × 109/L) and the median PLT was 89x109/L (range, 30-401 × 109/L); the median WBC and PLT \counts in the TPO group were 4.65 × 109/L (range, 0.99-23.63 × 109/L) and 86 × 109/L (range, 5-512 × 109/L), respectively. Patients in the TPO or eltrombopag group did not experience serious side effects after drug administration, and the difference in side effects on liver and kidney function between the two groups was not statistically significant. Eltrombopag is safe and similarly promotes platelet engraftment to thrombopoietin after allogeneic HSCT.

Abstract LB066: Acute systemic beta-adrenergic receptor activation to improve graft composition and outcomes in hematopoietic stem cell transplantation

Abstract Background: Graft-versus-host disease (GvHD) and relapse persist as significant hurdles in achieving successful outcomes following allogeneic hematopoietic cell transplantation (alloHCT). The composition of the graft plays a substantial role in influencing transplant outcomes. Higher numbers of naïve CD4 and naïve CD8 T cells correlate with increased GvHD risk, conversely, elevated numbers of NK cells are associated with enhanced graft-versus-leukemia (GvL) effects. Acute systemic β-adrenergic receptor activation triggers the mobilization of favorable effector lymphocytes into the bloodstream, leading to a significant alteration in the composition of circulating immune cells. Aim: This study investigated whether infusion with the non-selective beta-agonist isoproterenol (ISO), following granulocyte colony-stimulating factor (G-CSF) mobilization, would enhance human peripheral blood hematopoietic cell (PBHC) grafts and improve transplant outcomes in NSG mice. Methods: Ten healthy volunteers received ISO infusion (50 ng/kg/min) for 20 minutes after 5 days of G-CSF. Blood samples were collected before and during the last 5 minutes of ISO infusion. Results: ISO infusion increased the total number of G-CSF-mobilized CD34 cells (28±13 cell/µl to 32±13 cells/µl) and significantly improved G-CSF-mobilized PBHC composition, increasing favorable graft cell subsets—NK cells (9.5% to 27.9%) and γδ T cells (5.0% to 7.5%)—and reducing unfavorable graft components—B cells (12.6% to 7.7%), naïve CD4 (18.1% to 11.2%), and naïve CD8 (8.9% to 5.8%) T cells (all p&amp;lt;0.05). NSG mice receiving G-CSF+ISO mobilized grafts exhibited lower GvHD (P=0.012) and extended survival (median survival: G-CSF alone = 45 days, G-CSF+ISO = 78 days) compared to mice receiving grafts mobilized by G-CSF alone. No difference in human CD45 engraftment was observed between the groups, with ~50% engraftment in both groups of mice. Upon challenge with the K562 chronic myeloid leukemia cell line, 42% of NSG-Tg(Hu-IL15) mice receiving G-CSF+ISO mobilized grafts were alive with low tumor burden at day 40, compared to 15% of mice receiving G-CSF mobilized grafts. In vitro, PBHC mobilized by G-CSF+ISO demonstrated an 8-fold increase in cytolysis against K562 compared to PBHC mobilized by G-CSF only (P=0.0002). Conclusion: ISO infusion post-G-CSF treatment favorably enhances graft composition, mitigates GvHD, prolongs survival, and augments GvL effects. Our findings suggest that acute systemic beta-adrenergic receptor activation could be a valuable strategy to enhance outcomes in alloHCT. Citation Format: Helena Batatinha, Grace M. Niemiro, Nicole Pena, Giovannah Hoskin, Preteesh Mylabathula, Forrest Baker, Tiffany Zuniga, Kyle Smith, Douglass Diak, Michael Seckeler, Emmanuel Katsanis, Richard Simpson. Acute systemic beta-adrenergic receptor activation to improve graft composition and outcomes in hematopoietic stem cell transplantation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB066.

Abstract 2957: Senescence of stromal, endothelial, and myeloid cells in the tumor microenvironment has distinct effects on cancer progression

Abstract Accumulation of senescent cells, undermining the function of vital organs, is a culprit of aging. The effects of senescence in different types of cells on tumor growth and metastasis remain incompletely characterized. Cell senescence has been shown to result from inactivation of Telomerase (TERT), an enzyme that maintains telomere length and has obscure roles in regulating gene expression and supporting mitochondrial function. As we reported previously, knockout (KO) of Tert gene in mesenchymal stromal cells (MSC) of Pdgfra+ or Pdgfrb+ lineages leads to premature replicative stromal cell senescence in adipose tissue. To assess the effect of senescence in endothelial and myeloid cells, we also created mice with Tert KO driven by the Tie2e promoter or the LysM promoter, respectively. Here, to investigate the effect of these three KOs on cancer, we used syngeneic graft models of breast, prostate, and pancreatic carcinoma. Overall, Tert KO in cells of Pdgfra+, Pdgfrb+, Tie2e+, or LysM+ lineage had a suppressive effect on tumor growth. The strongest tumor suppression effect of Tert KO was observed in female mice orthotopically grafted with E0771 breast cancer cells. Intermediate suppressive effects of Tert KO were observed in mice orthotopically grafted with KPC pancreatic ductal adenocarcinoma cells, whereas the effect on RM1 prostate cancer cells grafts in male mice was the least significant. MSC Tert KO and myeloid Tert KO also suppressed the growth of breast and prostate cells grafts. Importantly, spontaneous metastases to the liver were induced by Tie2e-Tert KO in all mice with pancreatic KPC grafts. Analysis of adipose tissue in this endothelial senescence model revealed vasculature abnormality, leakiness, and tissue hypoxia, which provides a mechanistic explanation for increased tumor dissemination. In contrast, LysM-Tert KO did not promote KPC metastases, consistent with the lack of contribution of myeloid cells to the vasculature. Pdgfrb-Tert KO in the KPC model resulted in liver metastases observed for some but not all mice, consistent with the role of MSC in supporting vascular integrity. To test an independent model of replicative MSC senescence, we exhausted their pool by several cycles of ganciclovir treatment in mice expressing thymidine kinase under the control of Pdgfrb promoter. Upon KPC grafting in this model, reduced primary pancreatic tumor growth was also observed and liver metastases were also induced. We conclude that senescence of distinct cells in the tumor microenvironment affects early and late stages of cancer progression differently. Specifically, our data indicate that vascular cell senescence suppresses tumor growth but promotes metastases. These findings are important to consider as new approaches designed to mitigate cell senescence are investigated in the context of cancer. Citation Format: Joseph Rupert, Zhanguo Gao, Yongmei Yu, Mikhail Kolonin. Senescence of stromal, endothelial, and myeloid cells in the tumor microenvironment has distinct effects on cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2957.

Long-term observation of polycaprolactone small-diameter vascular grafts with thickened outer layer and heparinized inner layer in rabbit carotid arteries

In our previous study, the pristine bilayer small-diameter in situ tissue engineered vascular grafts (pTEVGs) were electrospun from a heparinized polycaprolactone (PCL45k) as an inner layer and a non-heparinized PCL80k as an outer layer in the thickness of about 131 μm and 202 μm, respectively. However, the hydrophilic enhancement of inner layer stemmed from the heparinization accelerated the degradation of grafts leading to the early formation of arterial aneurysms in a period of 3 months, severely hindering the perennial observation of the neo-tissue regeneration, host cell infiltration and graft remodeling in those implanted pTEVGs. Herein to address this drawback, the thickness of the outer layers was increased with PCL80k to around 268 μm, while the inner layer remained unchangeable. The thickened TEVGs named as tTEVGs were evaluated in six rabbits via a carotid artery interpositional model for a period of 9 months. All the animals kept alive and the grafts remained patent until explantation except for one whose one side of arterial blood vessels was occluded after an aneurysm occurred at 6 months. Although a significant degradation was observed in the implanted grafts at 9 month, the occurrence of aneurysms was obviously delayed compared to pTEVGs. The tissue stainings indicated that the endothelial cell remodeling was substantially completed by 3 months, while the regeneration of elastin and collagen remained smaller and unevenly distributed in comparison to autologous vessels. Additionally, the proliferation of macrophages and smooth muscle cells reached the maximum by 3 months. These tTEVGs possessing a heparinized inner layer and a thickened outer layer exhibited good patency and significantly delayed onset time of aneurysms.

Inpatient Rehabilitation of Hematopoietic Stem Cell Transplant Patients: Managing Challenging Impairments and Medical Fragility.

Hematopoietic stem cell transplants play an important role in the treatment of cancer, particularly hematologic malignancies. These patients can encounter functional impairments unique to hematopoietic stem cell transplant, including deconditioning, cancer-related fatigue, steroid myopathy, graft versus host disease, and capillary leak syndrome. Medical fragility and increased risk of infection may make rehabilitation challenging on the acute care and postacute care settings. Patients admitted to acute inpatient rehabilitation experience a high rate of transfer to the primary acute service and high rate of mortality after transfer back. Physical medicine and rehabilitation physicians can use a number of strategies to mitigate these patients' risk of medical complications including evidence-based predictive models to assist with postacute rehabilitation triage, physiatry-led consult-based rehabilitation, and oncology hospitalist comanagement on inpatient rehabilitation.

Monitoring of Red Cell Donor Chimerism in Oncohematological Patients After Allogeneic Hematopoietic Stem Cell Transplantation

Background. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a definitive therapy for patients with different oncological and hematological diseases. The study of red cell chimerism is a crucial process for diagnosing transplant engraftment and functioning during the post-transplantation period.&#x0D; Aim. To assess the effect of immunohematological (АВО and HLA donor–recipient matching) and medical (conditioning regimens) parameters on the onset time of post-transplantation donor chimerism which is determined by RBC antigens.&#x0D; Materials &amp; Methods. The study enrolled 54 patients at the Kirov Research Institute of Hematology and Transfusiology in Russia (25 female and 29 male patients) aged 3–60 years (median 32 years). All of them received allo-HSCT in 2013–2021. Acute leukemias were identified in 39 patients, 8 patients were reported to have malignant lymphoproliferative diseases, 3 patients had myeloproliferative neoplasms, and 4 patients were diagnosed with aplastic anemia. RBC antigens of donors and recipients were analyzed by gel hemagglutination using Bio-Rad (USA) reagents and equipment.&#x0D; Results. The onset time of donor chimerism depends neither on the degree of HLA donor–recipient matching, nor on conditioning regimen. Donor chimerism in recipients with major ABO-incompatibility occurs significantly later than in patients with minor АВО-incompatibility and ABO-identity.&#x0D; Conclusion. Monitoring of post-transplantation donor chimerism is an important diagnostic and prognostic tool to assess donor hematopoietic cell engraftment, hematologic recovery, graft rejection, and relapse of the disease. After allo-HSCT, first donor red cells occur in pairs with major АВО-incompatibility later than in pairs with minor АВО-incompatibility or ABO antigen compatibility. Other immunohematological and medical parameters do not affect the development rate of donor chimerism determined by RBC antigens.

Sulfur Switches for Responsive Peptide Materials.

There is considerable recent interest in the synthesis and development of peptide-based materials as mimics of natural biological assemblies that utilize proteins and peptides to form organized structures and develop beneficial properties. Due to their potential compatibility with living organisms, synthetic peptide materials are also being developed for applications such as cell grafting, therapeutic delivery, and implantable diagnostic devices. One desirable feature for such applications is the ability to design materials that can respond to stimuli by changes in their structure or properties under biologically relevant conditions. Peptide and protein assemblies can respond to stimuli, such as changes in temperature, solution pH, ions present in media, or interactions with other biomacromolecules. An exciting area of emerging research is focused on how biology uses the chemistry of sulfur-containing amino acids as a means to regulate biological processes. These concepts have been utilized and expanded in recent years to enable the development of peptide materials with readily switchable properties.The incorporation of sulfur atoms in polypeptides, peptides, and proteins provides unique sites that can be used to alter the physical and biological properties of these materials. Sulfur-containing amino acid residues, most often cysteine and methionine, are able to undergo a variety of selective chemical and enzyme-mediated reactions, which can be broadly characterized as redox or alkylation processes. These reactions often proceed under physiologically relevant conditions, can be reversible, and are significant in that they can alter residue polarity as well as conformations of peptide chains. These sulfur-based reactions are able to switch molecular and macromolecular properties of peptides and proteins in living systems and recently have been applied to synthetic peptide materials. Naturally occurring "sulfur switches" can be reversible or irreversible and are often triggered by enzymatic activity. Sulfur switches in peptide materials can also be triggered in vitro using oxidation/reduction and alkylation as well as photochemical reactions. The application of sulfur switches to peptide materials has greatly expanded the scope of these switches due to the ability to readily incorporate a wide variety of noncanonical sulfur-containing synthetic amino acids.Sulfur switches have been shown to provide considerable potential to reversibly alter peptide material properties under mild physiologically relevant conditions. An important molecular feature of sulfur-containing amino acid residues was found to be the location of sulfur atoms in the side chains. The variation of sulfur atom positions from the backbone by single bond lengths was found to significantly affect polypeptide chain conformations upon oxidation-reduction or alkylation/dealkylation reactions. With the successful adaptation of sulfur switches to peptide materials, future studies can explore how these switches affect how these materials interact with biological systems. This Account provides an overview of the different types of sulfur switch reactions found in biology and their properties and the elaboration of these switches in synthetic systems with a focus on recent developments and applications of reversible sulfur switches in peptide materials.

Post-transplant cyclophosphamide versus anti-thymocyte globulin after reduced intensity peripheral blood allogeneic cell transplantation in recipients of matched sibling or 10/10 HLA matched unrelated donors: final analysis of a randomized, open-label, multicenter, phase 2 trial

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is not established after reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) from fully matched donors. This was a randomized, open-label, multicenter, phase 2 trial. All patients received a RIC regimen with fludarabine, intravenous busulfan for 2 days (Flu-Bu2), and a peripheral blood stem cell (PBSC) graft from a matched related or 10/10 HLA-matched unrelated donor. Patients were randomly assigned to receive anti-thymocyte globulin (ATG) 5 mg/kg plus standard GVHD prophylaxis or PTCy 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis. The primary endpoint was the composite endpoint of GVHD- and relapse-free survival (GRFS) at 12 months after HSCT. Eighty-nine patients were randomly assigned to receive either PTCy or control prophylaxis with ATG. At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group (P = 0.99). Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group (P = 0.27). The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups. Although the primary objective was not met, PTCy is effective for GVHD prophylaxis in patients receiving Flu-Bu2 conditioning with a PBSC graft from a fully matched donor and was well tolerated in term of adverse events and quality of life. This trial was registered at clinicaltrials.gov: NCT02876679.

Comparing the effect of intravenous versus intracranial grafting of mesenchymal stem cells against parkinsonism in a rat model: Behavioral, biochemical, pathological and immunohistochemical studies.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Currently applied therapeutic protocols are limited to improve the motor functions of patients. Therefore, seeking alternative regimes with better therapeutic impact is crucial. This study aims to validate the therapeutic impact of mesenchymal stem cell injection using two delivery methods, intracranial administration and intravenous administration, on rotenone (ROT)-induced PD model in rats. Our work included behavioral, biochemical, histological, and molecular investigations. Open field test (OFT) and rotarod tests were applied. Important oxidative stress, antioxidant and proinflammatory markers were monitored. Substantia Nigra and Striatum tissues were examined histologically and the molecular expression of DOPA decarboxylase, Tyrosine hydroxylase, and α-synuclein in neurons in these tissues were investigated. Our results showed that MSC grafting improved motor and memory impairments and oxidative stress status that were observed after ROT administration. Additionally, BM-MSCs application restored SOD and CAT activities and the levels of DA, L-Dopa, IL6, IL1β, and TNFα. Moreover, MSC grafting overwhelmed the pathological changes induced by ROT and normalized the expression of Tyrosine hydroxylase, DOPA decarboxylase, and α-synuclein towards the control values in the Nigral and Striatal tissues of male rats. Conclusively, both administration routes improved motor function, protection of the nigrostriatal system, and improved striatal dopamine release. The observed beneficial effect of applying MSCs suggests potential benefits in clinical applications. No significant differences in the outcomes of the treatment would favor a certain way of MSC application over the other. However, the intravenous delivery method seems to be safer and more feasible compared to the intrastriatal method.

Molecular Retention Limitations for Prevascularized Subcutaneous Sites for Islet Transplantation.

Beta cell replacement therapies utilizing the subcutaneous space have inherent advantages to other sites: the potential for increased accessibility, noninvasive monitoring, and graft extraction. Site prevascularization has been developed to enhance islet survivability in the subcutaneous zone while minimizing potential foreign body immune responses. Molecular communication between the host and prevascularized implant site remains ill-defined. Poly(ethylene oxide)s (PEOs) of various hydrated radii (i.e., ∼11-62 Å) were injected into prevascularized subcutaneous sites in C57BL/6 mice, and the clearance and organ biodistribution were characterized. Prevascularization formed a barrier that confined the molecules compared with the unmodified site. Molecular clearance from the prevascularized site was inversely proportional to the molecular weight. The upper limit in molecular size for entering the vasculature to be cleared was determined to be 35 kDa MW PEO. These findings provide insight into the impact of vascularization on molecular retention at the injection site and the effect of molecular size on the mobility of hydrophilic molecules from the prevascularized site to the host. This information is necessary for optimizing the transplantation site for increasing the beta cell graft survival.

Graft-derived neurons and bystander effects are maintained for six months after human iPSC-derived NESC transplantation in mice’s cerebella

Machado-Joseph disease (MJD) is a neurodegenerative disorder characterized by widespread neuronal death affecting the cerebellum. Cell therapy can trigger neuronal replacement and neuroprotection through bystander effects providing a therapeutic option for neurodegenerative diseases. Here, human control (CNT) and MJD iPSC-derived neuroepithelial stem cells (NESC) were established and tested for their therapeutic potential. Cells’ neuroectodermal phenotype was demonstrated. Brain organoids obtained from the Control NESC showed higher mRNA levels of genes related to stem cells' bystander effects, such as BDNF, NEUROD1, and NOTCH1, as compared with organoids produced from MJD NESC, suggesting that Control NESC have a higher therapeutic potential. Graft-derived glia and neurons, such as cells positive for markers of cerebellar neurons, were detected six months after NESC transplantation in mice cerebella. The graft-derived neurons established excitatory and inhibitory synapses in the host cerebella, although CNT neurons exhibited higher excitatory synapse numbers compared with MJD neurons. Cell grafts, mainly CNT NESC, sustained the bystander effects through modulation of inflammatory interleukins (IL1B and IL10), neurotrophic factors (NGF), and neurogenesis-related proteins (Msi1 and NeuroD1), for six months in the mice cerebella. Altogether this study demonstrates the long-lasting therapeutic potential of human iPSC-derived NESC in the cerebellum.

Auto-Occlusive Lidocaine 7% and Tetracaine 7% Cream has Greater Pain Reduction Effects in Comparison with Lidocaine 4% Cream during Laser CO2 Dermabrasion Procedure in Preparation of Non-Cultured Autologous Epidermal Cell Grafting for Repigmentation in Vitiligo Subjects. An Intrasubject Pilot Evaluation Study

Introduction: Autologous non-cultured epidermal cell graft is a complex but promising technique in the treatment of vitiligo. Affected vitiligo areas should be de-epithelialized using an ablative Laser CO2 prior healthy epidermal cell inoculation. The dermabrasion (DA) procedure could be painful for the patient. To reduce the discomfort of this step topical anaesthesia is very often required. Topical anaesthetics available differ for composition, concentration of active anaesthetic molecules and methods of application (occlusion or not). An auto occlusive film-forming cream containing Lidocaine 7% and Tetracaine 7% (Pl-C) has shown in previous trials to be very effective in reducing discomfort during dermatological painful procedures like phototherapy, laser-conducted tattoo removal and laser resurfacing for skin ageing. Study Aim: To compare the clinical efficacy of Pl-C with Lidocaine 4% cream (As-C) in reducing the pain during Laser DA procedures in vitiligo subjects in preparation of autologous non-cultured epidermal transplantation. Subjects and Methods: We performed a prospective intra-subject randomized cases series in 7 subjects (4 men and 3 women) with segmental vitiligo with symmetrical lesions suitable for autologous non-cultured epidermal transplantation. Before the DA procedures the Pl-C or As-C were applied in a randomized fashion over the vitiligo areas to be treated. Pl-C was applied for 20 min without occlusion. The product was removed before the Laser procedure. As-C cream was applied for 30 min with occlusive band and then removed before the procedure. The treated skin regions had a mean area of 72±50 cm2; (range: 10 to 150 cm2). The primary outcome was the 100-mm Visual Analogue Scale (VAS) for patient-assessed pain evaluation with 0 mm value means no pain at all and 100 mm representing the worst possible pain. Results: Just after the Laser CO2 DA procedure the VAS score in PL-C area was 32±7 mm and 58±8 mm in As-C treated areas. This difference (-25±4 mm; 95% CI: from -16 to -35 mm) was highly statistically significant (p=0.0001) and clinically relevant (higher than the minimum clinically significant difference). Conclusion: The Lidocaine 7% and Tetracaine 7% auto occlusive cream is more effective than lidocaine 4% cream in reducing the pain associated with Laser CO2 DA procedures in preparation of skin autologous transplantation in vitiligo subjects.

Grafted human-induced pluripotent stem cells-derived oligodendrocyte progenitor cells combined with human umbilical vein endothelial cells contribute to functional recovery following spinal cord injury

BackgroundSpinal cord injury (SCI) is a devastating disease that causes extensive damage to oligodendrocytes and neurons leading to demyelination and axonal degeneration. In this study, we co-transplanted cell grafts containing oligodendrocyte progenitor cells (OPCs) derived from human-induced pluripotent stem cells (iPSCs) combined with human umbilical vein endothelial cells (HUVECs), which were reported to promote OPCs survival and migration, into rat contusion models to promote functional recovery after SCI.MethodsOPCs were derived from iPSCs and identified by immunofluorescence at different time points. Functional assays in vitro were performed to evaluate the effect of HUVECs on the proliferation, migration, and survival of OPCs by co-culture and migration assay, as well as on the neuronal axonal growth. A combination of OPCs and HUVECs was transplanted into the rat contusive model. Upon 8 weeks, immunofluorescence staining was performed to test the safety of transplanted cells and to observe the neuronal repairment, myelination, and neural circuit reconstruction at the injured area; also, the functional recovery was assessed by Basso, Beattie, and Bresnahan open-field scale, Ladder climb, SEP, and MEP. Furthermore, the effect of HUVECs on grafts was also determined in vivo.ResultsData showed that HUVECs promote the proliferation, migration, and survival of OPCs both in vitro and in vivo. Furthermore, 8 weeks upon engraftment, the rats with OPCs and HUVECs co-transplantation noticeably facilitated remyelination, enhanced functional connection between the grafts and the host and promoted functional recovery. In addition, compared with the OPCs-alone transplantation, the co-transplantation generated more sensory neurons at the lesion border and significantly improved the sensory functional recovery.ConclusionsOur study demonstrates that transplantation of OPCs combined with HUVECs significantly enhances both motor and sensory functional recovery after SCI. No significance was observed between OPCs combined with HUVECs group and OPCs-alone group in motor function recovery, while the sensory function recovery was significantly promoted in OPCs combined with HUVECs groups compared with the other two groups. These findings provide novel insights into the field of SCI research.