The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.

/pdf/mesenchymal-and-haematopoietic-stem-cells-form-a-unique-bone-3477057m0k.pdf

Mesenchymal and haematopoietic stem cells form a unique bone marrow niche

Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.

The worldwide incidence of bone disorders and conditions has trended steeply upward and is expected to double by 2020, especially in populations where aging is coupled with increased obesity and poor physical activity. Engineered bone tissue has been viewed as a potential alternative to the conventional use of bone grafts, due to their limitless supply and no disease transmission. However, bone tissue engineering practices have not proceeded to clinical practice due to several limitations or challenges. Bone tissue engineering aims to induce new functional bone regeneration via the synergistic combination of biomaterials, cells, and factor therapy. In this review, we discuss the fundamentals of bone tissue engineering, highlighting the current state of this field. Further, we review the recent advances of biomaterial and cell-based research, as well as approaches used to enhance bone regeneration. Specifically, we discuss widely investigated biomaterial scaffolds, micro- and nano-structural properties of these scaffolds, and the incorporation of biomimetic properties and/or growth factors. In addition, we examine various cellular approaches, including the use of mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), adult stem cells, induced pluripotent stem cells (iPSCs), and platelet-rich plasma (PRP), and their clinical application strengths and limitations. We conclude by overviewing the challenges that face the bone tissue engineering field, such as the lack of sufficient vascularization at the defect site, and the research aimed at functional bone tissue engineering. These challenges will drive future research in the field.

/pdf/bone-tissue-engineering-recent-advances-and-challenges-4gc67py9d5.pdf

Bone Tissue Engineering: Recent Advances and Challenges

Significant efforts have been directed to understanding the factors that influence the lineage commitment of stem cells. This paper demonstrates that cell shape, independent of soluble factors, has a strong influence on the differentiation of human mesenchymal stem cells (MSCs) from bone marrow. When exposed to competing soluble differentiation signals, cells cultured in rectangles with increasing aspect ratio and in shapes with pentagonal symmetry but with different subcellular curvature—and with each occupying the same area—display different adipogenesis and osteogenesis profiles. The results reveal that geometric features that increase actomyosin contractility promote osteogenesis and are consistent with in vivo characteristics of the microenvironment of the differentiated cells. Cytoskeletal-disrupting pharmacological agents modulate shape-based trends in lineage commitment verifying the critical role of focal adhesion and myosin-generated contractility during differentiation. Microarray analysis and pathway inhibition studies suggest that contractile cells promote osteogenesis by enhancing c-Jun N-terminal kinase (JNK) and extracellular related kinase (ERK1/2) activation in conjunction with elevated wingless-type (Wnt) signaling. Taken together, this work points to the role that geometric shape cues can play in orchestrating the mechanochemical signals and paracrine/autocrine factors that can direct MSCs to appropriate fates.

https://www.pnas.org/content/pnas/107/11/4872.full.pdf

Geometric cues for directing the differentiation of mesenchymal stem cells.

Adult skeletal muscle in mammals is a stable tissue under normal circumstances but has remarkable ability to repair after injury. Skeletal muscle regeneration is a highly orchestrated process invol...

Satellite Cells and the Muscle Stem Cell Niche

https://www.pure.ed.ac.uk/ws/files/14186931/A_Perivascular_Origin_for_Mesenchymal_Stem_Cells_in_Multiple_Human_Organs.pdf

A perivascular origin for mesenchymal stem cells in multiple human organs


 Background: Despite advances in cancer diagnosis and therapy, high-grade serous ovarian cancer (HGSC) is often diagnosed when spread to multiple intraperitoneal areas; it is prone to metastasize to adipose-rich tissues such as the omentum. To gain a deeper understanding of the molecular determinants of the HGSC milieu, we carried out a single-cell analysis of primary and metastatic tumors of HGSC. Thus, our aim is to identify molecular mechanisms that lead to immunosuppressive mechanisms of HGSC in primary and metastatic tumors of HGSC.
 Methods: Fresh HGSC surgical samples from 19 patients were collected right after surgery, dissociated, and then frozen. For single-cells analysis, cells were sorted by a viability dye and CD45+/- populations followed by Single cell 10 × 3’v3 protocol (10X Genomics) and sequenced using the NovaSeq6000 S2 sequencer. Cell Ranger toolkit v3.1.0 (10x Genomics) was applied for data processing, followed by further downstream analysis using multiple packages from R Package Seurat.
 Results: To elucidate the cellular heterogeneity of HGSC, we analyzed 100,480 cells, including epithelial, lymphoid, and myeloid populations; these were identified and represented across all patients. We explored the epithelial compartment further, including a total of 21,144 cells. Given the importance of metastatic lesions for the treatment and outcome of patients with HGSC, we examined expression programs among primary and omentum tumors as well treated and untreated tumors. The major differences between primary and omental metastatic tumors included enrichment of EMT pathways and angiogenesis, as well as a decrease in the IFNα and IFNγ response in the omentum. IFNα and IFNγ response pathways were also upregulated in primary treated (P-NACT) tumors, when compared with primary untreated (P-UT) tumors. To explore the immune compartment, we clustered the immune cells across patients in 28 sub-clusters, including 19 sub-clusters of T-cells and Natural Killer cells. Altogether, the immune infiltration on P-UT indicated an immune infiltrate environment and the composition of P-UT was highly enriched in lymphoid cells with a late stage of differentiation. This finding was also demonstrated by the analysis of T cell trajectories, with a clear definition that CD8 and CD4 cells from P-UT tumors are in a late/final and exhausted stage of differentiation, while post-NACT tumors (independent of tissue type) are in early stages (naïve/central memory). The measurement of a dysfunctional score showed that P-UT tumors have the highest scores, indicating a potential increase in tumor reactivity in P-UT tumors.
 Conclusions: Collectively, these data indicate that HGSC primary and omentum tumors are very distinct niches for immune cells, with primary being much more dysfunctional than omentum tissue, which could indicate that the application of immunotherapies would have different impacts in variable niches of HGSC.
 Citation Format: Elaine Stur, Fuduan Peng, Pang-ning Teng, Emine Bayraktar, Min Hu, Sara Corvigno, David J. Brown, Sanghoon Lee, Kathleen N. Moore, Nicholas W. Bateman, Kathleen M. Darcy, George L. Maxwell, Thomas Conrads, Nicole Fleming, Nicholas Navin, Linghua Wang, Anil K. Sood. The dynamic immune behavior of primary and metastatic tumors of ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5782.

Pang-ning Teng

Papers

A perivascular origin for mesenchymal stem cells in multiple human organs

Abstract 5782: The dynamic immune behavior of primary and metastatic tumors of ovarian cancer