Current Stem Cell Research & Therapy - Volume 17, Issue 3, 2022

Stem cell therapy is widely regarded as a promising strategy in regenerative medicine, yet the therapeutic effects of stem cells in vivo are limited by many factors when applied without additional factors, such as poor cell engraftment, uncontrolled differentiation, and unclear cell fates and niches. The emergence of nanotechnology has provided several solutions for these problems. Nanomaterial-based cell labeling and tracking have been extensively investigated in recent decades, and many innovative and multifunctional nanomaterials have been used to reveal the fate of stem cells, allowing more efficient, sensitive, and accurate imaging/tracking strategies for stem cells to be achieved. Nanomaterials enhance stem cell therapy by incorporating or integrating with stem cells and, as scaffolds or substrates, nanomaterials with antioxidant properties that can be used as graft coatings show great promise for clinical transformation. However, current reviews on the subject tend to focus on the various effects of nanomaterials on stem cells and are less concerned with their application to stem cell therapy. Accordingly, we herein present a review of progress in the application of nanomaterials in stem cell therapy over the last three years, which we hope will be of benefit to a comprehensive understanding of nanomaterial-mediated stem cell therapy from lab to pre-clinical practice.

Adult stem cells like mammary and mesenchymal stem cells have received significant attention because these stem cells possess therapeutic potential in treating many animal diseases. These cells can be administered in an autologous or allogenic fashion, either freshly isolated from the donor tissue or previously cultured and expanded in vitro. The expansion of adult stem cells is a prerequisite before therapeutic application because sufficient numbers are required in dosage calculation. Stem cells directly and indirectly (by secreting various growth factors and angiogenic factors called secretome) act to repair and regenerate injured tissues. Recent studies on mammary stem cells showed in vivo and in vitro expansion ability by removing the blockage of asymmetrical cell division. Compounds like purine analogs (xanthosine, xanthine, and inosine) or hormones (progesterone and bST) help increase stem cell population by promoting cell division. Such methodology of enhancing stem cell number, either in vivo or in vitro, may help in preclinical studies for translational research like treating diseases such as mastitis. The application of mesenchymal stem cells has also been shown to benefit mammary gland health due to the ‘homing’ property of stem cells. In addition to that, the multiple positive effects of stem cell secretome are on mammary tissue; healing and killing bacteria is novel in the production of quality milk. This systematic review discusses some of the studies on stem cells that have been useful in increasing the stem cell population and increasing mammary stem/progenitor cells. Finally, we provide insights into how enhancing mammary stem cell population could potentially increase terminally differentiated cells, ultimately leading to more milk production.

Background: The main cause of progressive vision impairment in retinal degenerative diseases is the dysfunction of photoreceptors and the underlying retinal pigment epithelial cells. The inadequate regenerative capacity of the neural retina and lack of established therapeutic options demand the development of clinical-grade protocols to halt the degenerative process in the eye or replace the damaged cells by using stem cell-derived products. Recently, stem cell-based regenerative therapies have been at the forefront of clinical investigations for retinal dystrophies. Objective: This article will review different stem cell-based therapies currently employed for retinal degenerative diseases, recent clinical trials, and major challenges in the translation of these therapies from bench to bedside. Methodology: A systematic literature review was conducted to identify potentially relevant articles published in MEDLINE/PubMed, Embase, ClinicalTrials.gov, Drugs@FDA, European Medicines Agency, and World Health Organization International Clinical Trials Registry Platform. Results: Transplantation of healthy cells to replace damaged cells in the outer retina is a clinically relevant concept because the inner retina that communicates with the visual areas of the brain remains functional even after the photoreceptors are completely lost. Various methods have been established for the differentiation of pluripotent stem cells into different retinal cell types that can be used for therapies. Factors released from transplanted somatic stem cells showed trophic support and photoreceptor rescue during the early stages of the disease. Several preclinical and phase I/II clinical studies using terminally differentiated photoreceptor/retinal pigment epithelial cells derived from pluripotent stem cells have shown proof of concept for visual restoration in Age-related Macular Degeneration (AMD), Stargardt disease, and Retinitis Pigmentosa (RP). Conclusion: Cell replacement therapy has great potential for vision restoration. The results obtained from the initial clinical trials are encouraging and indicate its therapeutic benefits. The current status of the therapies suggests that there is a long way to go before these results can be applied to routine clinical practice. Input from the ongoing multicentre clinical trials will give a more refined idea for the future design of clinical-grade protocols to transplant GMP level HLA matched cells.

The advent of organoids has renewed researchers' interest in in vitro cell culture systems. A wide variety of protocols, primarily utilizing pluripotent stem cells, are under development to improve organoid generation to mimic organ development. The complexity of organoids generated is greatly influenced based on the method used. Understanding the process of kidney organoid formation gives developmental insights into how renal cells form, mature, and interact with the adjacent cells to form specific spatiotemporal structural patterns. This knowledge can bridge the gaps in understanding in vivo renal developmental processes. Evaluating genetic and epigenetic signatures in specialized cell types can help interpret the molecular mechanisms governing cell fate. In addition, development in single-cell RNA sequencing, 3D bioprinting and microfluidic technologies has led to better identification and understanding of a variety of cell types during differentiation and designing of complex structures to mimic the conditions in vivo. While several reviews have highlighted the application of kidney organoids, there is no comprehensive review of various methodologies specifically focusing on kidney organoids. This review summarizes the updated differentiation methodologies, applications, and challenges associated with kidney organoids. Here we have comprehensively collated all the different variables influencing the organoid generation.

Background: The consistent, self-renewal capability and wide-ranged differentiation potential during specific physiologic conditions mark stem cells as a novel candidate not only for biomedical research and regenerative therapy but also as an alternative source in research related to life sciences. This vital and distinct characteristic of stem cells enables them to offer unprecedented hope in treating many diseases and disorders, which are otherwise difficult to treat. Several efforts are still being undertaken to enhance the efficiency of MSCs for better therapeutic applications. Objective: In the recent past, several studies have been conducted regarding the isolation of stem cells from diverse sources and are being used clinically in veterinary regenerative therapy. However, to date, only a few systemic studies are available. This study provides a comprehensive analysis of the findings from basic and applied research conducted on stem cell therapeutics with particular emphasis on animals. Result: On the basis of their sources, stem cells can be classified as adult or embryonic stem (ES) cells. Physiologically, the ES cells have the capability to differentiate into all body cells and develop into the normal adult organism, whereas adult stem cells serve as a repair system by restoring damaged tissues of the body. The adult stem cells referred to as Mesenchymal stem cells (MSCs) can be derived from various adult body organs, whereas embryos give rise to embryonic stem cells. MSCs possess the unique property of proliferation, trans-differentiation, and secretion of important biomolecules to create a microenvironment, which is immunosuppressive and stimulates native MSCs of damaged tissue. MSCs being immunocompromised cells can be used in autologous as well as in allogenic mode. Conclusion: In veterinary therapeutics, MSCs equipped with engineering and pharmaceutical modifications are offered as potential candidates in the treatment of wound healing, nerve injury, bone/ligament injury, etc., and also bear a great hope for the improvement of udder health and milk production in animals.

Pluripotent stem cells (PSCs) have unlimited capacity for self-renewal and differentiation so that they can potentially produce any cell or tissue of animal’s body. The PSCs derived from livestock represents a more appropriate model than a rodent for investigating human diseases due to their higher anatomical and physiological resemblance with human. Apart from that, livestock PSCs hold immense promises for innovative therapies, transgenic animal production and their biomedical interest. The realization of the full potential of PSCs, however, depends on the elucidation of the molecular mechanisms which play a critical role in the maintenance of pluripotency and reprogramming procedure remains poorly understood in livestock which in turn impedes the generation of true PSCs and their usage for clinical research. An in-depth understanding of pluripotency is extremely essential for improving health and welfare of livestock animals. Therefore, the present review focuses on the milestone achievements of PSCs in livestock animals and their potential application in health and production of livestock.

Precise and site-specific genome editing through application of emerging and modern gene engineering techniques, namely zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR/ Cas9) have swiftly progressed the application and use of the stem cell technology in the sphere of in-vitro disease modelling and regenerative medicine. Genome editing tools facilitate the manipulation of genes in various types of cells with target-specific nucleases. These tools aid in elucidating the genetics and etiology behind different diseases and have immense promise as novel therapeutics for correcting the genetic mutations, making alterations, and curing diseases permanently, which are not responding and resistant to traditional therapies. These genome engineering tools have evolved in the field of biomedical research and have also been shown to have a significant improvement in clinical trials. However, their widespread use in the research revealed potential safety issues, which need to be addressed before implementing such techniques for clinical purposes. Significant and valiant attempts need to be made in order to surpass those hurdles. The current review outlines the advancements of several genome engineering tools and describes suitable strategies for their application towards regenerative medicine.

Spinal cord injury is a devastating condition that is critically challenging and progressive, needing immediate medical attention due to its complex pathophysiology and affecting the social status and economic burden. Stem cell therapy has been the emerging therapeutic trend to treat various diseases for decades. Mesenchymal stem cells pose more advantages over other stem cells in immune-modulation, immune evasiveness, self-renewal, multipotency, etc. Due to various issues in the recent past related to allogenic transplants, ethical concerns in obtaining tissues and adult cells, host immune response, GMP grade production and certification, cell-derived products or cell secretome have proven to be a promising approach and have been implicated in many studies and also in many clinical trials. Utilization of these human MSC-derived exosomes/extracellular vesicles in spinal cord injury has also been demonstrated in many pre-clinical animal models. It is now proven to be therapeutically more efficient and safer than cell therapy. This review focuses on employing human MSC derived EVs for SCI and continues to elucidate the recent advances and emerging EVs trends from other cell types. We discuss biomaterial-based synergistic intervention, mention mimetics and nanovesicles and finally touch upon safety concerns in EV therapy.

Graphene and its derivatives have application potential in many areas such as environmental technology, catalysis, biomedicine, and in particular, stem cell-based differentiation and regenerative therapies. Mesenchymal stem cell transplantation has emerged as a potential therapy for some diseases, such as acute kidney damage, liver failure and myocardial infarction. However, the poor survival of transplanted stem cells in such applications has significantly limited their therapeutic effectiveness. Graphene-based materials can improve the therapeutic efficacy of stem cells as they prevent the death of implanted cells by attaching them prior to implantation and increasing their paracrine secretion. In this review, we will highlight a number of recent studies that have investigated the potential use of graphene or its derivatives in stem cell applications and the prevention of transplanted stem cells from cell death, thereby improving their therapeutic efficacy.