Current Stem Cell Research & Therapy - Volume 18, Issue 2, 2023

Induced pluripotent stem cells (iPSCs) are a type of pluripotent stem cells induced by somatic cells. It was found that differentiated cells could be reprogrammed to a pluripotent state by the expression of the four transcription factors such as Oct3/4, Sox2, c-Myc, and Klf4. This technology can be applied to reprogramme the patient cells into iPSCs, which further be induced into research-required cells or tissues. Nowadays, a great number of reprogramming methods and various types of somatic cells can be used to produce iPSCs. The advancement of this technology provides a promising pathway to disease models building, drug development, and the corresponding cell-based therapy. Alzheimer's diseases (AD) and Parkinson's diseases (PD) are complex diseases affected by many factors, including genetic and environmental factors. Until now, there are no effective treatments to reverse these diseases because the pathogenesis of these complex diseases is still not well understood. One important reason is that the existing disease model cannot fully recapitulate the pathologies of these multifactorial associated diseases and iPSCs have the potential to resolve this difficulty. In this review, we discuss the application progress of iPSCs in AD and PD, including disease modeling, drug development, and cellbased therapies.

A common surgical disease, intervertebral disc degeneration (IVDD), is increasing at an alarming rate in younger individuals. Repairing damaged intervertebral discs (IVDs) and promoting IVD tissue regeneration at the molecular level are important research goals. Exosomes are extracellular vesicles (EVs) secreted by cells and can be derived from most body fluids. Mesenchymal stem cell-derived exosomes (MSC-exos) have characteristics similar to those of the parental MSCs. These EVs can shuttle various macromolecular substances, such as proteins, messenger RNAs (mRNAs), and microRNAs (miRNAs) and regulate the activity of recipient cells through intercellular communication. Reducing inflammation and apoptosis can significantly promote IVD regeneration to facilitate the repair of the IVD. Compared with MSCs, exosomes are more convenient to store and transport, and the use of exosomes can prevent the risk of rejection with cell transplantation. Furthermore, MSC-exo-mediated treatment may be safer and more effective than MSC transplantation. In this review, we summarize the use of bone marrow mesenchymal stem cells (BMSCs), adipose-derived mesenchymal stem cells (AMSCs), nucleus pulposus mesenchymal stem cells (NPMSCs), and stem cells from other sources for tissue engineering and use in IVDD. Here, we aim to describe the role of exosomes in inhibiting IVDD, their potential therapeutic effects, the results of the most recent research, and their clinical application prospects to provide an overview for researchers seeking to explore new treatment strategies and improve the efficacy of IVDD treatment.

HIV is a virus that targets and hijacks the immune cells of the host. It multiplies by attacking the helper T-lymphocytes. HIV has remained one of the most difficult and dangerous infections in the world due to the inability to find a successful treatment and a lack of access to medical care. When the virus reaches the body, dendritic cells are the first cells it encounters. DCs have been identified as one of the most effective mediators of immune responses, implying a promising strategy against viral infection. The current state of knowledge about the function of dendritic cells and their subsets is critical for using their full potential as a candidate for the development of an HIV vaccine. Despite extensive efforts, a reliable vaccine with the fewest side effects has yet to be found, and further research is needed to find a dependable and efficient vaccine. The extent to which dendritic cell-based therapy is used to treat HIV was investigated in this study. As the virus attacks the host immune system, the dendritic cells can trigger an immune response against HIV-1 infection.

Hearing loss is one of the most important public health matters worldwide, severely affecting people's social, psychological, and cognitive development. The perception of sound, movement, and balance in vertebrates depends on a special sensory organ called the cochlea, which contains hair cells and supporting cells in the inner ear. Genetic factors, epigenetics, the use of ototoxic drugs (some antibiotics and chemotherapeutics), noise, infections, or even aging can cause loss of hair cells and their related primary neurons, leading to sensorineural hearing loss. Although a sensorineural hearing loss, also known as permanent hearing loss, is treated with hearing aids and cochlear implants, treatment methods are limited. Since even the best implant cannot exhibit the characteristics of the original ear, the permanent sensory deficit will be permanent. For this reason, it has become important to develop regenerative treatment methods to regenerate and replace lost or damaged hair cells and neurons. Developments in stem cell technology have led to promising studies in regenerating damaged/lost hair cells or neurons with endogenous or exogenous cell-based therapies. Epigenetic mechanisms can turn hearing-related genes on and off and determine which proteins to copy. In addition, due to gene silencing, gene replacement, and CRISPR/CAS9 technology, gene therapy methods have accelerated, and studies have been carried out to treat dominant and recessive mutations that cause genetic-induced hearing loss or increase hair cell regeneration. In this paper, potential gene therapy and stem cell applications in the acquisition of cochlear function, which causes sensorineural hearing loss, and the difficulties encountered in these applications are compiled from a bioengineering perspective.

Background: Cardiovascular disease (CVD) is one of the world’s leading causes of increased morbidity and mortality. Current interventions for CVD, including percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG), carry certain risks and complications, which may also affect the patient’s quality of life. It is important to minimize those risks and complications while speeding up the recovery. Insulin Growth Factor-1 (IGF-1) is a growth factor responsible for cellular migration, proliferation, differentiation, and angiogenesis, which supports cardiovascular regeneration. Methods: In light of the current trend of regenerative medicine, the present review aims to pool data relating to the incorporation of IGF-1 in regenerative medicine and provide input on the current research gaps and concerns arising on translating this approach from benchwork into clinical settings. Results: Using the keywords IGF-1 ‘OR’ Insulin Growth Factor 1 ‘AND’ Mesenchymal Stem Cells ‘AND’ Tissue Healing from 2009 to 2020, we identified 160 and 52 from Medline and PubMed, screening out 202 articles due to non-fulfilment of the inclusion criteria. Conclusion: Incorporating IGF-1 into regenerative and personalized medicine may be promising for treating CVD; however, the concerns include the role of IGF-1 in inducing cancer growth and its ability to migrate to the specific site of injury, especially for those who present with multiple pathologies should be addressed prior to its translation from bench work into clinical settings.

Background: It has been observed that bone marrow-derived mesenchymal stem cells (MSCs) migrate towards the injured spinal cord and promote functional recovery when systemically transplanted into the traumatized spinal cord. However, the mechanisms underlying their migration to the spinal cord remain poorly understood. Methods: In this study, we systemically transplanted GFP- and luciferase-expressing MSCs into rat models of spinal cord injury and examined the role of the stromal cell-derived factor 1 (SDF-1)/CXCR4 axis in regulating the migration of transplanted MSCs to the spinal cord. After intravenous injection, MSCs migrated to the injured spinal cord where the expression of SDF-1 was increased. Spinal cord recruitment of MSCs was blocked by pre-incubation with an inhibitor of CXCR4. Their presence correlated with morphological and functional recovery. In vitro, SDF-1 or cerebrospinal fluid (CSF) collected from SCI rats promoted a dose-dependent migration of MSCs in culture, which was blocked by an inhibitor of CXCR4 or SDF-1 antibody. Results and Conclusion: The study suggests that SDF-1/CXCR4 interactions recruit exogenous MSCs to injured spinal cord tissues and may enhance neural regeneration. Modulation of the homing capacity may be instrumental in harnessing the therapeutic potential of MSCs.

Background: Increased oxygen species levels can induce mitochondrial DNA damage and chromosomal aberrations and cause defective stem cell differentiation, leading finally to senescence of stem cells. In recent years, several studies have reported that antioxidants can improve stem cell survival and subsequently affect the potency and differentiation of these cells. Finding factors, which reduce the senescence tendency of stem cells upon expansion, has great potential for cellular therapy in regenerative medicine. This study aimed to evaluate the effects of L-carnitine (LC) on the aging of C-kit+ hematopoietic progenitor cells (HPCs) via examining the expression of some signaling pathway components. Methods: For this purpose, bone marrow resident C-kit+ HPCs were enriched by the magnetic-activated cell sorting (MACS) method and were characterized using flow cytometry as well as immunocytochemistry. Cells were treated with LC, and at the end of the treatment period, the cells were subjected to the realtime PCR technique along with a western blotting assay for measurement of the telomere length and assessment of protein expression, respectively. Results: The results showed that 0.2 mM LC caused the elongation of the telomere length and increased the TERT protein expression. In addition, a significant increase was observed in the protein expression of p38, p53, BCL2, and p16 as key components of the telomere-dependent pathway. Conclusion: It can be concluded that LC can increase the telomere length as an effective factor in increasing the cell survival and maintenance of the C-kit+ HPCs via these signaling pathway components.

Background: Uncontrollable inflammatory response following ectopic engineered cartilage implantation is devastating to the aesthetic and functional outcomes of the recipients. Adipose stem cells (ASCs) have a good immunomodulatory capacity via a paracrine mechanism. However, works of literature are scarce regarding ASC modulation in ectopic engineered cartilage regeneration in vivo. This study aims to explore how ASCs modulate the inflammatory response after engineered cartilage implantation and affect the implants in a nonchondrogenic milieu in large immunocompetent animals. Methods: Porcine engineered elastic cartilages were cultured in vitro for 3 weeks with chondrocyte cell sheeting technology and then assigned into two groups: ASCs and Control (saline injection). All samples (n= 6 per group) were autologously implanted into different subcutaneous pockets, and a single dose of ASCs was injected at three points around the implant. All samples were harvested after 2 weeks in vivo for analysis. Results: In the examination of inflammation, we observed reduced inflammatory cell infiltration and improved M2 macrophage polarization in the implanted engineered cartilage with ASC injection compared to the control. There were also enhanced anti-inflammatory cytokines and reduced proinflammatory cytokines inside and adjacent to the implants, while in serum, there were no significant differences. In the examination of the cartilage quality, there were significant increases in cartilage extracellular matrix and chondrogenic factors, and the elastic cartilage phenotype was maintained compared to control. Conclusion: This study finds that a single dose of ASCs can promote ectopic cartilage regeneration by modulating inflammation and enhancing cartilage matrix synthesis in a porcine model.&

Introduction: Acute Myocardial Infarction (AMI) has been classified as a prevalent condition threatening human health. This study sought to explore the effects of bone marrow mesenchymal stem cells (BMSCs)-extracellular vesicles (EVs) on cardiomyocyte apoptosis and autophagy induced by ischemia- hypoxia (I/H). Materials and Methods: EVs were isolated from BMSCs using ultracentrifugation. The I/H cardiomyocyte model was established and cultured with EVs to evaluate the internalization of EVs by the cardiomyocyte line, apoptosis, proliferation, and autophagy of the cardiomyocyte line. The targeting relationship between miR-144-3p and ROCK1 was verified. EVs were isolated after transfection of BMSCs with the miR-144-3p inhibitor to evaluate the effect of miR-144-3p on the cardiomyocyte line. Results and Discussion: After overexpression of ROCK1 in the I/H cardiomyocyte line treated with EVs, the I/H cardiomyocyte line apoptosis and autophagy were determined. BMSCs-EVs suppressed I/Hinduced apoptosis and autophagy of the cardiomyocyte line. BMSCs-EVs carried miR-144-3p into the I/H cardiomyocyte line, and the down-regulation of miR-144-3p in EVs partially inverted the suppression of apoptosis and autophagy of the I/H cardiomyocyte line induced by EVs. Our findings denoted that miR- 144-3p targeted ROCK1. Overexpression of ROCK1 partially inverted the inhibition of EVs on I/H cardiomyocyte line apoptosis and autophagy. BMSCs-EVs-derived miR-144-3p targeted ROCK1 to radically activate the PI3K/AKT/mTOR pathway. Conclusion: Overall, our study elicited that BMSCs-EVs carried miR-144-3p into the I/H cardiomyocyte line to target ROCK1 and stimulate the PI3K/AKT/mTOR pathway, thus inhibiting I/H-induced cardiomyocyte line apoptosis and autophagy.

Background: A growing number of studies have demonstrated that mesenchymal stem cells (MSCs) can effectively regulate the progression of multiple autoimmune diseases and can respond positively to mechanical stimulation by ultrasound in an in vitro setting to improve transplantation efficacy. Objective: The aim of this study was to activate hUC-MSCs by pretreatment with low-intensity focused pulsed ultrasound (LIFPUS) in an in vitro environment and transplant them into a rat model of EAT via tail vein. To investigate the efficacy and potential mechanism of action of hUC-MSCs in the treatment of EAT. Methods: In this study, 40 female lewis rats were divided into control, EAT, hUC-MSCs treatment and LIFPUS pretreatment transplantation group. EAT models were established by subcutaneous multi-point injection of PTG+Freund's adjuvant, and the primary hUC-MSCs were treated with different gradients of LIFPUS irradiation or sham irradiation in an in vitro environment and screened by Western Blot (WB), flow cytology cycle analysis, and cellular immunofluorescence to find the optimal treatment parameters for LIFPUS to promote cell proliferation. After tail vein injection of different pretreatment groups of hUC-MSCs, Homing sites of hUC-MSCs in vivo, circulating autoantibody expression levels and local thyroid histopathological changes were assessed by enzyme-linked immunosorbent assay (ELISA), spleen index, tissue hematoxylin-eosin (HE) staining and immunohistochemistry. The expression levels of apoptotic proteins Bcl-2, Bax and endoplasmic reticulum stress-related proteins Chop and EIF2α in thyroid tissue were also examined by WB. Results: LIFPUS can effectively stimulate hUC-MSCs in vitro to achieve the most optimal proliferative and secretory activity. In the EAT model, hUC-MSCs can effectively reduce thyroid cell apoptosis, improve thyroid function and reduce excessive accumulation of autoimmune antibodies in the body. in comparison, the LIFPUS pretreatment group showed a more favorable treatment outcome. Further experiments demonstrated that hUC-MSCs transplantation may effectively inhibit the apoptotic state of thyroid follicles and follicular epithelial cells by down-regulating the unfolded protein reaction (UPR) of the PERK pathway, thus providing a therapeutic effect for AIT. Conclusion: hUC-MSCs can effectively reverse the physiological function of EAT thyroid tissue and reduce the accumulation of circulating antibodies in the body. in comparison, hUC-MSCs under LIFPUS pretreatment showed more desirable therapeutic potential. hUC-MSCs transplanted under LIFPUS pretreatment may be a new class of safe therapeutic modality for the treatment of AIT.

Objective: This study aimed to compare the results of stem cell therapy with mini-sling for women’s stress urinary incontinence. Methods: This study was a parallel groups noninferiority randomized clinical trial. Patients with pure stress urinary incontinence who did not improve after three months of conservative and medical therapy were included. Patients were divided into two groups mini-sling insertion or peri-urethral injection of the autologous mucosa stem cell with simple equal randomization. Standard Incontinence Impact Questionnaire (IIQ) for patients’ satisfaction as well as objective Marshal Test as primary outcomes were compared. Results: From October 2016 to March 2018, 30 patients (mean age of 52 years) were randomly divided equally into two groups. Finally, a negative Marshal test was observed in 73% of the stem cell group vs. 80% in the mini-sling group (p = 0.6). The mean decrease in the IIQ results was 12 points in the stem cell group vs. 25 points in the mini-sling group (p = 0.05). Favorable results at 6 m and 26 m follow-up were 40% vs. 80% (p = 0.06) and 53% vs. 60% (p = 0.7) in stem cell and mini-sling group, respectively. Patients in the mini-sling group experienced a higher rate of dyspareunia. Intervention time and hospital stay were 6.46 ± 1.24 minutes vs. 19.40 ± 4.30 minutes (p = 0.001) and 4.33 ± 1.23 vs. 9.20 ± 3.16 hours (p = 0.001) in stem cell and mini-sling groups, respectively. Conclusion: Results of the periurethral injection of the autologous adult mucosa-derived stem cells are not inferior to the less invasive mini-sling procedure; while, the stem cell group showed shorter intervention time and hospital stay as well as fewer complications. This noninferiority pilot randomized trial compared the results of stem cell therapy with mini-sling surgery and showed that in the medium-term followup, the results are comparable.