Adipose Stem Cells in Regenerative Medicine: Looking Forward

Over the last decade, stem cell-based regenerative medicine has progressed to clinical testing and therapeutic applications. The applications range from infusions of autologous and allogeneic stem cells to stem cell-derived products. Adult stem cells from adipose tissue (ASCs) show significant promise in treating autoimmune and neurodegenerative diseases, vascular and metabolic diseases, bone and cartilage regeneration and wound defects. The regenerative capabilities of ASCs in vivo are primarily orchestrated by their secretome of paracrine factors and cell-matrix interactions. More recent developments are focused on creating more complex structures such as 3D organoids, tissue elements and eventually fully functional tissues and organs to replace or repair diseased or damaged tissues. The current and future applications for ASCs in regenerative medicine are discussed here.

Pulmonary Mesenchymal Stem Cells in Mild Cases of COVID-19 Are Dedicated to Proliferation; In Severe Cases, They Control Inflammation, Make Cell Dispersion, and Tissue Regeneration

Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have potent self-renewal capacity and differentiate into multiple cell types. For many reasons, these cells are a promising therapeutic alternative to treat patients with severe COVID-19 and pulmonary post-COVID sequelae. These cells are not only essential for tissue regeneration; they can also alter the pulmonary environment through the paracrine secretion of several mediators. They can control or promote inflammation, induce other stem cells differentiation, restrain the virus load, and much more. In this work, we performed single-cell RNA-seq data analysis of MSCs in bronchoalveolar lavage samples from control individuals and COVID-19 patients with mild and severe clinical conditions. When we compared samples from mild cases with control individuals, most genes transcriptionally upregulated in COVID-19 were involved in cell proliferation. However, a new set of genes with distinct biological functions was upregulated when we compared severely affected with mild COVID-19 patients. In this analysis, the cells upregulated genes related to cell dispersion/migration and induced the γ-activated sequence (GAS) genes, probably triggered by IFNGR1 and IFNGR2. Then, IRF-1 was upregulated, one of the GAS target genes, leading to the interferon-stimulated response (ISR) and the overexpression of many signature target genes. The MSCs also upregulated genes involved in the mesenchymal-epithelial transition, virus control, cell chemotaxis, and used the cytoplasmic RNA danger sensors RIG-1, MDA5, and PKR. In a non-comparative analysis, we observed that MSCs from severe cases do not express many NF-κB upstream receptors, such as Toll-like (TLRs) TLR-3, -7, and -8; tumor necrosis factor (TNFR1 or TNFR2), RANK, CD40, and IL-1R1. Indeed, many NF-κB inhibitors were upregulated, including PPP2CB, OPTN, NFKBIA, and FHL2, suggesting that MSCs do not play a role in the “cytokine storm” observed. Therefore, lung MSCs in COVID-19 sense immune danger and act protectively in concert with the pulmonary environment, confirming their therapeutic potential in cell-based therapy for COVID-19. The transcription of MSCs senescence markers is discussed.

TrpA1 is a shear stress mechanosensing channel regulating intestinal homeostasis in Drosophila

Adult stem cells are essential for maintaining normal tissue homeostasis and supporting tissue repair. Although genetic and biochemical programs controlling adult stem cell behavior have been extensively investigated, how mechanosensing regulates stem cells and tissue homeostasis is not well understood. Here, we show that shear stress can activate enteroendocrine cells, but not other gut epithelial cell types, to regulate intestine stem cell-mediated gut homeostasis. This shear stress sensing is mediated by transient receptor potential A1 (TrpA1), a Ca2+-permeable ion channel expressed only in enteroendocrine cells among all gut epithelial cells. Genetic depletion of TrpA1 or modification of its shear stress sensing function causes reduced intestine stem cell proliferation and intestine growth. We further show that among the TrpA1 splice variants, only select isoforms are activated by shear stress. Altogether, our results suggest the naturally occurring mechanical force such as fluid passing generated shear stress regulates intestinal stem cell-mediated tissue growth by activating enteroendocrine cells, and Drosophila TrpA1 as a new shear stress sensor.

Ginsenoside Rg1 as a Potential Regulator of Hematopoietic Stem/Progenitor Cells

Ginsenoside Rg1 (Rg1), a purified, active component of the root or stem of ginseng, exerts positive effects on mesenchymal stem cells (MSCs). Many recent studies have found that hematopoietic stem cells (HSCs), which can develop into hematopoietic progenitor cells (HPCs) and mature blood cells, are another class of heterogeneous adult stem cells that can be regulated by Rg1. Rg1 can affect HSC proliferation and migration, regulate HSC/HPC differentiation, and alleviate HSC aging, and these findings potentially provide new strategies to improve the HSC homing rate in HSC transplantation and for the treatment of graft-versus-host disease (GVHD) or other HSC/HPC dysplasia-induced diseases. In this review, we used bioinformatics methods, molecular docking verification, and a literature review to systematically explore the possible molecular pharmacological activities of Rg1 through which it regulates HSCs/HPCs.

PPIA and YWHAZ Constitute a Stable Pair of Reference Genes during Electrical Stimulation in Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are multipotent adult stem cells with great potential in regenerative medicine. One method for stimulating proliferation and differentiation of MSCs is via electrical stimulation (ES). A valuable approach for evaluating the response of MSCs to ES is to assess changes in gene expression, relative to one or more reference genes. In a survey of 25 publications that used ES on cells, 70% selected GAPDH as the reference gene. We conducted a study to assess the suitability of six potential reference genes on an immortalized human MSC line following direct current ES at seeding densities of 5000 and 10,000 cells/cm2. We employed three methods to validate the most stable reference genes from qRT-PCR data. Our findings show that GAPDH and ACTB exhibit reduced stability when seeded at 5000 cell/cm2. In contrast, we found that the most stable genes across both plating densities and stimulation regimes were PPIA and YWHAZ. Thus, in ES gene expression studies in MSCs, we support the use of PPIA and YWHAZ as an optimal reference gene pair, and discourage the use of ACTB and GAPDH at lower seeding densities. However, it is strongly recommended that similar verification studies are carried out based on cell type and different ES conditions.

Application of Nanomaterials in Regulating the Fate of Adipose-derived Stem Cells

Adipose-derived stem cells are adult stem cells which are easy to obtain and multi-potent. Stem-cell therapy has become a promising new treatment for many diseases, and plays an increasingly important role in the field of tissue repair, regeneration and reconstruction. The physicochemical properties of the extracellular microenvironment contribute to the regulation of the fate of stem cells. Nanomaterials have stable particle size, large specific surface area and good biocompatibility, which has led them being recognized as having broad application prospects in the field of biomedicine. In this paper, we review recent developments of nanomaterials in adipose-derived stem cell research. Taken together, the current literature indicates that nanomaterials can regulate the proliferation and differentiation of adipose-derived stem cells. However, the properties and regulatory effects of nanomaterials can vary widely depending on their composition. This review aims to provide a comprehensive guide for future stem-cell research on the use of nanomaterials.

An Evolving Role for the Long Non-Coding RNA H19 in Aging and Senescence

The long non-coding RNA (lncRNA) H19 is a maternally imprinted gene transcript that, in conjunction with the neighboring Igf2 gene, is critical in controlling embryonic growth. Loss of H19 results in fetal overgrowth associated with Beckwith Weidemann syndrome, while elevated H19 occurs in human cancers. In the adult, H19 functions in cancer cells where it promotes migration and is correlated with poor prognosis, and in adult stem cells where it is a key regulator of cell fate decisions during differentiation. While the function of H19 in primary somatic cells has not been defined, a reduction in the abundance of H19 has been reported during senescence in endothelial cells. Given the critical importance of H19 in cell fate decisions, it is likely that understanding the precise function of H19 in somatic cells in general and why reduced levels occur with cellular senescence will provide novel insights into both somatic cell maintenance and the senescence program. Towards this end, we examined the role of H19 in somatic cell growth using cardiac interstitial fibroblasts. Our results indicate that H19 is not only vital for somatic cell proliferation and survival, but that depletion of H19 leads to cell cycle arrest and the formation of abnormal nuclei resulting in senescent cells. We are defining both the upstream regulators of H19 and the downstream mediators of senescence following H19 depletion. Overall, these results indicate an essential role for H19 in cell cycle progression, chromatin structure, and possibly proper mitotic division.

Effects of Caloric Restriction on the Epigenetic Landscape of Hematopoietic Stem Cells

During aging, alterations of hematopoietic stem cells are associated with functional decline of the blood system. Caloric restriction (CR) interventions have been reported to improve adult stem cells in other tissue types during aging so we sought to evaluate the effects of CR on the aged HSC compartment. We find significant epigenetic alterations in HSCs isolated from aged mice after life-long CR compared to ad libitum fed aged mice. We further evaluated the epigenetic landscapes and functional potential of aged HSCs shortly after allowing life-long CR mice access to ad libitum food. We uncover epigenetic modification associated with functional alterations of the HSCs, defining potential mechanisms by which restrictions in food consumption affect the aging hematopoietic compartment.

Challenges of stem cell application in research and clinical practice – an update

There are multiple possible applications of stem cells in medicine, from cell-based therapies for degenerative and dystrophic conditions, through novel approaches in cancer treatment, to in vitro organ printing. However, there are still several challenges that need to be overcame before stem cells therapies can be successfully introduced worldwide on a large scale. These include sourcing of stem cells, preventing their aberrant progression and ethical concerns regarding their use in animals and humans. Among the multiple stem cell types present in the human organism from the period of embryonic development to adulthood, this review focuses on the three types that gain the most attention in relation to modern research: embryonic stem cells, induced pluripotent stem cells and adult stem cells. There are a number of obstacles that need to be removed before these cells can be widely applied in clinical practice, including the choice of the perfect source of stem cells, full elucidation of the mechanisms of stem cell differentiation and plasticity, and minimization of adverse side effect potential. Nonetheless, the focus of the scientific community on the topic of stem cells remains unhindered, bringing hope that all of the possible concerns will be addressed in the future.