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BackgroundAlthough studies suggest a deficiency in stem cell numbers in chronic airway diseases such as chronic obstructive pulmonary disease (COPD), the role of bronchial epithelial progenitor/stem (P/S) cells is not clear. The objectives of this study were to investigate expression of progenitor/stem (P/S) cell markers, cytokeratin (CK) 5, CK14 and p63 in bronchial epithelial explants and cell cultures obtained from smokers with and without COPD following multiple outgrowths, and to study this effect on bronchial epithelial cell (BEC) proliferation.MethodsBronchial epithelial explants were dissected from lung explants and cultured on coverslips. Confluent cultures were obtained after 3–4 weeks’ (transfer, Tr1), explants were then transferred and cultured for a second (Tr2) and third (Tr3) time, respectively. At each stage, expression of CK5, CK14 and p63 in explants and BEC were determined by immunostaining. In parallel experiments, outgrowing cells from explants were counted after 4wks, and explants subsequently transferred to obtain new cultures for a further 3 times.ResultsAs the transfer number advanced, CK5, CK14 and p63 expression was decreased in both explants and BEC from both smokers without COPD and patients with COPD, with a more pronounced decrease in BEC numbers in the COPD group. Total cell numbers cultured from explants were decreased with advancing outgrowth number in both groups. Smoking status and lung function parameters were correlated with reduced P/S marker expression and cell numbers.ConclusionOur findings suggest that the number of P/S cells in airway epithelium may play a role in the pathogenesis of COPD, as well as a role in the proliferation of airway epithelial cells, in vitro.

Prostate cancer (PCa) is the most common cancer and second leading cause of cancer death in American men. Most patients with metastatic disease respond initially to androgen deprivation therapy (ADT), but almost inevitably progress to castration resistant prostate cancer (CRPC). Identification of markers and drivers of mCRPC that (a) represent a progenitor-type cancer cell population (b) persist in castration resistant disease (c) are actionable targets expressed on the cell surface, and (d) are induced by hypoxia, is required to facilitate the development of novel targeted therapies. We identified prostatic acid phosphatase (PAP), particularly the transmembrane form (TMPAP), as one such potential target. PAP is both a phosphatase and a 5'ectonucleotidase that generates adenosine. We herein demonstrate that PAP is expressed early on during fetal development and persists in castration-resistant disease. The VCaP and VCaP-enzalutamide-resistant PCa cell lines express secretory (sPAP) and TMPAP. Androgens downregulate while hypoxia upregulates PAP expression. In vivo, PAP persists in hypoxic areas of castration-resistant tumors. Knockdown of PAP decreases VCaP migration and colony formation. Finally, treatment of VCaP tumor-bearing mice with inhibitors of adenosine receptors reduces tumor growth. This data demonstrates that TMPAP is a novel therapeutic target in advanced prostate cancer., Competing Interests: None., (AJCEU Copyright © 2024.)

Intervertebral disk (IVD) degeneration is one of the most common musculoskeletal disease. Current clinical treatment paradigms for IVD degeneration cannot completely restore the structural and biomechanical functions of the IVD. Bio-therapeutic techniques focused on progenitor/stem cells, especially IVD progenitor cells, provide promising options for the treatment of IVD degeneration. Endogenous repair is an important self-repair mechanism in IVD that can allow the IVD to maintain a long-term homeostasis. The progenitor cells within IVD play a significant role in IVD endogenous repair. Improving the adverse microenvironment in degenerative IVD and promoting progenitor cell migration might be important strategies for implementation of the modulation of endogenous repair of IVD. Here, we not only reviewed the research status of treatment of degenerative IVD based on IVD progenitor cells, but also emphasized the concept of endogenous repair of IVD and discussed the potential new research direction of IVD endogenous repair.

The SOXC group of transcription factors, composed of SOX4, SOX11, and SOX12, has evolved to fulfill key functions in cell fate determination. Expressed in many types of progenitor/stem cells, including skeletal progenitors, SOXC proteins potentiate pathways critical for cell survival and differentiation. As skeletogenesis unfolds, SOXC proteins ensure cartilage primordia delineation by amplifying canonical WNT signaling and antagonizing the chondrogenic action of SOX9 in perichondrium and presumptive articular joint cells. They then ensure skeletal elongation by inducing growth plate formation via enabling non-canonical WNT signaling. Human studies have associated SOX4 with bone mineral density and fracture risk in osteoporotic patients, and SOX11 with Coffin-Siris, a syndrome that includes skeletal dysmorphism. Meanwhile, in vitro and mouse studies have suggested important cell-autonomous roles for SOXC proteins in osteoblastogenesis. We here review current knowledge and gaps in understanding of SOXC protein functions, with an emphasis on the skeleton and possible links to osteoporosis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Tissue homeostasis depends on the balance between cell proliferation and differentiation. Thyroid hormones (THs), through binding to their nuclear receptors, can regulate the expression of many genes involved in cell cycle control and cellular differentiation. This can occur by direct transcriptional regulation or by modulation of the activity of different signaling pathways. Scope of review: In this review we will summarize the role of the different receptor isoforms in growth and maturation of selected tissues and organs. We will focus on mammalian tissues, and therefore we will not address the fundamental role of the THs during amphibian metamorphosis. Major conclusions: The actions of THs are highly pleiotropic, affecting many tissues at different developmental stages. As a consequence, their effects on proliferation and differentiation are highly heterogeneous depending on the cell type, the cellular context, and the developmental or transformation status. Both during development and in the adult, stem cells are essential for proper organ formation, maintenance and regeneration. Recent evidence suggests that some of the actions of the thyroid hormone receptors could be secondary to regulation of stem/progenitor cell function. Here we will also include the latest knowledge on the role of these receptors in proliferation and differentiation of embryonic and adult stem cells. General significance: The thyroid hormone receptors are potent regulators of proliferation and differentiation of many cell types. This can explain the important role of the thyroid hormones and their receptors in key processes such as growth, development, tissue homeostasis or cancer. This article is part of a Special Issue entitled Thyroid hormone signalling. [Copyright &y& Elsevier]

Normal endometrial growth is essential for embryonic implantation and maintenance of pregnancy. The uterine endometrium contains stem cells that are involved in tissue regeneration. Side population cells (SP cells) are an emerging cell population that may be responsible for the regeneration process of uterine endometrium. In this study, we investigated the changes in the distribution of SP cells using a mouse model of uterine endometrial injury that was induced by peritoneal injection of lipopolysaccharide (LPS). The uterine horns were collected 0, 6, 12, and 18 hours after LPS injection. ATP-binding cassette and sub-family G member 2 (Abcg2) is highly expressed on the cellular membrane of some stem and progenitor cells, and was used as a marker for SP cells. Immunohistochemistry demonstrated that Abcg2-positive cells were increased around the uterine endometrial glands from 6 to 12 h after LPS injection. The percentage of Abcg2-positive cells was calculated using flow cytometry. The percentage of stromal SP cells was significantly higher at 6 h after LPS injection, compared with the value before the injection (3.01 ± 0.41% vs. 1.63 ± 0.31%, P < 0.05). To evaluate the influence of ovarian hormones, we implanted pellets containing 17β-estradiol (0.1 mg), progesterone (10 mg), or a combination of 17β-estradiol and progesterone in the bilaterally ovariectomized mice. Ovariectomy abolished the increase in SP cells, which was restored by estradiol, but not by progesterone or the combination treatment. In conclusion, estrogen is required for the increase of SP cells, thereby leading to the regeneration of the uterine endometrium. [ABSTRACT FROM AUTHOR]

Abstract: Background: Small diameter characterizes epidermal progenitor/stem cells. We have developed Gravity Assisted Cell Sorting (GACS) to simply enrich small-sized epidermal progenitor/stem cells. Objective: The cells sorted by GACS were characterized by fluorescence-activated cell sorting analysis, and cultured for up to 7 weeks. The cultured cells were then used for reconstruction of skin equivalent. Methods: GACS was performed on primary cultures (primary cell) and passage 6–7 cultures (cultured cell) of keratinocytes. A keratinocyte suspension was sized into two groups: cells trapped by a 20μm filter (trapped cells), and cells flowing through both a 20 and 11μm filter (non-trapped cells). Results: In the primary cell groups, viability of the trapped cells was 62.5±7.2% compared to 77.0±3.7% for the non-trapped cells. In the cultured cell groups, viability of the trapped cells was 64.3±14.9%, compared to the non-trapped cells (93.1±2.0%). Flow cytometric analysis showed better discrimination by cell size between trapped and non-trapped cells in culture than in the primary cell suspension. Non-trapped cells contained a larger number of cells with high levels of α6 integrin and low levels of CD71 (α6 integrinbriCD71dim), indicating an enriched progenitor/stem cell population. The difference in these markers between the non-trapped and trapped cells was seen in both the primary and cultured cell groups although this difference was more distinct in cultured cells. Culture of both groups showed that cultures originating from the trapped cells senesced after approximately 15 days while the non-trapped keratinocytes grew for up to 40 days. Manufacture of an epidermis/dermal device (artificial skin) showed that non-trapped cells formed a significantly thicker epithelial layer than the trapped cells, demonstrating the enhanced regenerative capability of the smaller diameter, α6 integrinbriCD71dim cells separated by GACS. Conclusion: These results indicate that GACS is simple and useful technique to enrich for epidermal progenitor/stem cell populations, and is more efficient when used on cells in culture. [Copyright &y& Elsevier]

Oral mucosa progenitor/stem cells reside as a small-sized cell population that eventually differentiates concurrently with an increase in cell size. Activation of the mammalian target of rapamycin (mTOR) leads to an increase in cell size. We hypothesized that rapamycin, a specific inhibitor of mTOR, will maintain primary human oral keratinocytes as a small-sized, undifferentiated cell population capable of retaining their proliferative capacity. Primary, rapamycin-treated (2 nM, 20 nM) oral keratinocytes showed a diminished cell size that correlated with a higher clonogenicity, a longer-term proliferative potential, and a slower cycling cell population concurrent with decreased expression of a differentiation marker when compared with untreated cells. Only the 2-nM rapamycin-treated oral keratinocytes maintained their ability to regenerate oral mucosa in vitro after 15 weeks of culture. Rapamycin, a Food and Drug Administration-approved drug, may have applicability for use in creating a highly proliferative cell population for use in regenerative medicine. [ABSTRACT FROM AUTHOR]

The Notch signaling pathway regulates stem cell proliferation and differentiation in multiple tissues and organs, and is required for tissue maintenance. However, the role of Notch in regulation of olfactory epithelium (OE) progenitor/stem cells to maintain tissue function is still not clear. A recent study reported that leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is expressed in globose basal cells (GBCs) localized in OE. Through lineage tracing in vivo, we found that Lgr5 + cells act as progenitor/stem cells in OE. The generation of daughter cells from Lgr5 + progenitor/stem cells is delicately regulated by the Notch signaling pathway, which not only controls the proliferation of Lgr5 + cells and their immediate progenies but also affects their subsequent terminal differentiation. In conditionally cultured OE organoids in vitro, inhibition of Notch signaling promotes neuronal differentiation. Besides, OE lesion through methimazole administration in mice induces generation of more Notch1 + cells in the horizontal basal cell (HBC) layer, and organoids derived from lesioned OE possesses more proliferative Notch1 + HBCs. In summary, we concluded that Notch signaling regulates Lgr5 + GBCs by controlling cellular proliferation and differentiation as well as maintaining epithelial cell homeostasis in normal OE. Meanwhile, Notch1 also marks HBCs in lesioned OE and Notch1 + HBCs are transiently present in OE after injury. This implies that Notch1 + cells in OE may have dual roles, functioning as GBCs in early development of OE and HBCs in restoring the lesioned OE. Stem Cells 2018;36:1259-1272., (© AlphaMed Press 2018.)

Progenitor/stem cell (PSC) has shown great promise for generation in failing heart. Advances in PSC biology have greatly enhanced our understanding of how PSC self-renewal, migration, maintenance of stemness, and cell-fate commitment depend on the balance of complex signals in their microenvironment. Endogenous PSC exists within structural and functional units known as PSC niches, which play important roles in directing PSC behavior. Recent years have witnessed great progress in our understanding of the PSC niche in cardiovascular biology. PSC based therapy could lead to successful cardiac regeneration or repair. Realizing the potential of therapeutic strategies is based on 1) differentiation of the PSC into all of the cellular constituents of the heart; 2) release of paracrine/ autocrine factors from the PSC; 3) fusion of the PSC with the existing constituents of the heart; and 4) stimulation of endogenous repair (regeneration of PSC niches). Importantly, cardiac PSC niches contain supporting cells and these cell-cell interactions have crucial regulatory roles in PSC based therapy. These findings have important implications for heart development, bioengineering, and furthermore elucidate a broader dimension of PSC control within the niche toward cardiomyocyte phenotype.