Microenvironmental Views on Mesenchymal Stem Cell Differentiation in Aging

Abstract

Aging is characterized by common environmental changes, such as hormonal, immunologic, and metabolic disorders. These pathologic factors impair the capability of mesenchymal stem cells (MSCs) to generate and maintain functionalized tissue components, contributing to age-related tissue degeneration (e.g., osteoporosis). However, in organismal aging, whether the microenvironmental signals induce common or differential MSC compromise and how they interact at the molecular level in mediating the functional decline of MSCs are not fully understood. In this review, we discuss the respective contribution of microenvironmental pathologic factors to age-related MSC dysfunction-particularly, the shifted differentiation from osteoblasts to adipocytes of bone marrow-derived MSCs. The authors summarize recent works regarding mechanisms underlying MSC-biased differentiation under altered microenvironments, which involve the activation of key signaling pathways, intracellular oxidative stress, and posttranscriptional regulations. In addition, we compare the differential influences of systemic and local microenvironments on MSC differentiation based on our findings. The authors also propose strategies to rescue differentiation disorders of MSCs in aging via modulating microenvironments, by using signaling modulators, anti-inflammatory agents, antioxidants, and metabolic regulators and by promoting mobilization of systemic MSCs to local injury sites. The authors hope that these insights contribute to MSC-based organismal aging research and treatments.

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

“…Emerging evidence supports the hypothesis that accumulation of senescent cells or alteration of some age‐related molecules (e.g., miRNA, RNA, lipids, and proteins) packaged by exosomes in the bone microenvironment is the primary cause of osteoporosis (Farr et al., 2017; Gibon, Lu, & Goodman, 2016; Lim et al., 2017; Sui, Hu, Zheng, & Jin, 2016; Williams, Smith, Kumar, Vijayan, & Reddy, 2017). Targeting these exosomes, which act as important communicators between cells, may emerge as a new therapeutic approach for osteoporosis (Liu et al., 2017; Long et al., 2017; Nakano et al., 2016).…”

Role of the Cytokine-like Hormone Leptin in Muscle-bone Crosstalk with Aging

“…BMSCs isolated from older individuals are observed to have impaired proliferation, increased senescence, and reduced potential for osteoblastic differentiation. [32495051] It is certainly possible that some of these age-associated changes in BMSC function documented in older donors may be associated with alterations in factors associated with leptin signaling, such as microRNAs targeting the leptin receptor or molecules such as suppressor of cytokine signaling 3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B) that inhibit leptin signal transduction. [5253]…”

The effect of thymic mesenchymal stromal cells on arginase activity and nitric oxide produced by mouse macrophages

“…Thus, in the proinflammatory environment typical of aged organism, MSC may adopt immunosuppressive phenotype and attenuate inflammation. However, aging impairs MSC functions as well, leading to reduced proliferative activi ty, increased apoptosis and misdirected differentiation toward adipocytes [8].…”