Bone Marrow-Derived Mononuclear Cells in the Treatment of Neurological Diseases: Knowns and Unknowns.

Bone marrow-derived mononuclear cells (BMMNCs) have been used for decades in preclinical and clinical studies to treat various neurological diseases. However, there is still a knowledge gap in the understanding of the underlying mechanisms of BMMNCs in the treatment of neurological diseases. In addition, prerequisite factors for the efficacy of BMMNC administration, such as the optimal route, dose, and number of administrations, remain unclear. In this review, we discuss known and unknown aspects of BMMNCs, including the cell harvesting, administration route and dose; mechanisms of action; and their applications in neurological diseases, including stroke, cerebral palsy, spinal cord injury, traumatic brain injury, amyotrophic lateral sclerosis, autism spectrum disorder, and epilepsy. Furthermore, recommendations on indications for BMMNC administration and the advantages and limitations of BMMNC applications for neurological diseases are discussed. BMMNCs in the treatment of neurological diseases. BMMNCs have been applied in several neurological diseases. Proposed mechanisms for the action of BMMNCs include homing, differentiation and paracrine effects (angiogenesis, neuroprotection, and anti-inflammation). Further studies should be performed to determine the optimal cell dose and administration route, the roles of BMMNC subtypes, and the indications for the use of BMMNCs in neurological conditions with and without genetic abnormalities.

Clinical Study of Mesenchymal Stem/Stromal Cell Therapy for the Treatment of Frailty: A Proposed Experimental Design for Therapeutic and Mechanistic Investigation.

Frailty, a specific condition of increased vulnerability and reduced general health associated with aging in older people, is an emerging problem worldwide with major implications for clinical practice and public health. Recent preclinical and clinical studies have supported the safety of mesenchymal stem/stromal cells (MSCs) in the treatment of frailty. Comprehensive study is needed to assess the interrelationship between the condition of frailty and the effects of MSC-based therapy. This randomized controlled phase I/II trial aims to investigate the safety and potential therapeutic efficacy of the allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) in combination with the standard treatment for frailty in Vietnam. Moreover, this study describes the rationales, study designs, methodologies, and analytical strategies currently employed in stem cell research and clinical studies. The primary outcome measures will include the incidences of prespecified administration-associated adverse events and serious adverse events. The potential efficacy will be evaluated based on improvements in frailty conditions (including those determined through a physical examination, patient-reported outcomes, quality of life, immune markers of frailty, metabolism analysis, and cytokine markers from patient plasma). This clinical trial and stem cell analysis associated with patient sampling at different time points aim to identify and characterize the potential effects of UC-MSCs on improving frailty based on the stem cell quality, cytokine/growth factor secretion profiles of UC-MSCs, cellular senescence, and metabolic analysis of patient CD3+ cells providing fundamental knowledge for designing and implementing research strategies in future studies. Clinical Trials Registration Number: NCT04919135.

Standardized xeno- and serum-free culture platform enables large-scale expansion of high-quality mesenchymal stem/stromal cells from perinatal and adult tissue sources.

BACKGROUND AIMS: Mesenchymal stem/stromal cells (MSCs) are of interest for the treatment of graft-versus-host disease, autoimmune diseases, osteoarthritis and neurological and cardiovascular diseases. Increasing numbers of clinical trials emphasize the need for standardized manufacturing of these cells. However, many challenges related to diverse isolation and expansion protocols and differences in cell tissue sources exist. As a result, the cell products used in numerous trials vary greatly in characteristics and potency. METHODS: The authors have established a standardized culture platform using xeno- and serum-free commercial media for expansion of MSCs derived from umbilical cord (UC), bone marrow and adipose-derived (AD) and examined their functional characteristics. RESULTS: MSCs from the tested sources stably expanded in vitro and retained their biomarker expression and normal karyotype at early and later passages and after cryopreservation. MSCs were capable of colony formation and successfully differentiated into osteogenic, adipogenic and chondrogenic lineages. Pilot expansion of UC-MSCs and AD-MSCs to clinical scale revealed that the cells met the required quality standard for therapeutic applications. CONCLUSIONS: The authors' data suggest that xeno- and serum-free culture conditions are suitable for large-scale expansion and enable comparative study of MSCs of different origins. This is of importance for therapeutic purposes, especially because of the numerous variations in pre-clinical and clinical protocols for MSC-based products.

Differential Wound Healing Capacity of Mesenchymal Stem Cell-Derived Exosomes Originated From Bone Marrow, Adipose Tissue and Umbilical Cord Under Serum- and Xeno-Free Condition.

Exosomes are nano-scale and closed membrane vesicles which are promising for therapeutic applications due to exosome-enclosed therapeutic molecules such as DNA, small RNAs, proteins and lipids. Recently, it has been demonstrated that mesenchymal stem cell (MSC)-derived exosomes have capacity to regulate many biological events associated with wound healing process, such as cell proliferation, cell migration and blood vessel formation. This study investigated the regenerative potentials for cutaneous tissue, in regard to growth factors associated with wound healing and skin cell proliferation and migration, by exosomes released from primary MSCs originated from bone marrow (BM), adipose tissue (AD), and umbilical cord (UC) under serum- and xeno-free condition. We found crucial wound healing-mediated growth factors, such as vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2), hepatocyte growth factor (HGF), and platelet-derived growth factor BB (PDGF-BB) in exosomes derived from all three MSC sources. However, expression levels of these growth factors in exosomes were influenced by MSC origins, especially transforming growth factor beta (TGF-ß) was only detected in UCMSC-derived exosomes. All exosomes released by three MSCs sources induced keratinocyte and fibroblast proliferation and migration; and, the induction of cell migration is a dependent manner with the higher dose of exosomes was used (20 µg), the faster migration rate was observed. Additionally, the influences of exosomes on cell proliferation and migration was associated with exosome origins and also target cells of exosomes that the greatest induction of primary dermal fibroblasts belongs to BMMSC-derived exosomes and keratinocytes belongs to UCMSC-derived exosomes. Data from this study indicated that BMMSCs and UCMSCs under clinical condition secreted exosomes are promising to develop into therapeutic products for wound healing treatment.

Improvement in gross motor function and muscle tone in children with cerebral palsy related to neonatal icterus: an open-label, uncontrolled clinical trial.

BACKGROUND: Although stem cell transplantation has been successfully performed for cerebral palsy (CP) related to oxygen deprivation, clinical trials involving the use of stem cell transplantation for CP related to neonatal icterus have not been reported. The aim of this study was to evaluate the effectiveness of transplantation of autologous bone marrow mononuclear cell (BMMC) for improving gross motor function and muscle tone in children with CP related to neonatal icterus. METHODS: This open-label, uncontrolled clinical trial, which included 25 patients with CP related to neonatal icterus who had a Gross Motor Function Classification System (GMFCS) score between level II and level V, was conducted between July 2014 and July 2017 at Vinmec International Hospital (Vietnam). BMMC were harvested from the patients' iliac crests. Two procedures involving BMMC transplantation via the intrathecal route were performed: the first transplantation was performed at baseline, and the second transplantation was performed 6 months after the first transplantation. Gross motor function and muscle tone were measured at three time points (baseline, 6 months, and 12 months) using the Gross Motor Function Measure (GMFM) and the Modified Ashworth Scale. RESULTS: In this trial, we observed significant improvement in gross motor function and a significant decrease in muscle tone values. Total score on the 88-item GMFM (GMFM-88), scores on each GMFM-88 domain, and the 66-item GMFM (GMFM-66) percentile were significantly enhanced at 6 months and 12 months after the first transplantation compared with the corresponding baseline measurements (p-values < 0.05). In addition, a significant reduction was observed in muscle tone score after the transplantations (p-value < 0.05). CONCLUSION: Autologous BMMC transplantation can improve gross motor function and muscle tone in children with CP related to neonatal icterus. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03123562 . Retrospectively registered on December 26, 2017.

One-staged or two-staged surgery for perforated choledochal cyst with bile peritonitis in children? A single center experience with 27 cases.

PURPOSE: To report the authors' experience in the management of perforated choledochal cyst with bile peritonitis (PCC) in children. METHODS: Medical records of all children undergoing surgery for PCC at our hospital from May, 2005 to January, 2013 were reviewed. RESULTS: Twenty seven patients were identified, with a median age of 2 years. The clinical manifestations were abdominal pain (96.3 %), abdominal distention (92.6 %), vomiting (88.9 %), jaundice (74.1 %), fever (70.4 %), acholic stool (51.8 %), abdominal tenderness (92.6 %), peritoneal signs (74.1 %), and palpable mass (18.5 %). Duration of the acute symptoms ranged from 1 to 30 days (median 3 days). Median size of the choledochal cysts was 3 cm (range 1.5-18 cm). Before January 2008, four cases were treated by two-staged surgery and only one case by one-staged surgery. Since then, all remaining 22 cases were treated by the one-staged surgery. There was no anastomotic leakage and all patients were discharged in good health. The mean postoperative stay was 7.6 ± 2.5 days for the one-staged group. No complication was noted at a median follow-up of 24 months. CONCLUSIONS: One-staged definitive repair is feasible, safe and should be the treatment of choice for most cases of childhood PCC in experienced centers.