Age-associated changes in the ecological niche: implications for mesenchymal stem cell aging

Abstract

Adult stem cells are critical for organ-specific regeneration and self-renewal with advancing age. The prospect of being able to reverse tissue-specific post-injury sequelae by harvesting, culturing and transplanting a patient's own stem and progenitor cells is exciting. Mesenchymal stem cells have emerged as a reliable stem cell source for this treatment modality and are currently being tested in numerous ongoing clinical trials. Unfortunately, the fervor over mesenchymal stem cells is mitigated by several lines of evidence suggesting that their efficacy is limited by natural aging. This article discusses the mechanisms and manifestations of age-associated deficiencies in mesenchymal stem cell efficacy. A consideration of recent experimental findings suggests that the ecological niche might be responsible for mesenchymal stem cell aging.

Figure 1

Representative micrographs depicting morphological change after 21 days of exposure to differentiation media. Representative micrographs show anti-FABP4, anti-osteocalcin, anti-aggrecan and anti-cardiac myosin heavy chain staining in differentiating bone marrow-derived mesenchymal stem cells (BM-MSCs). BM-MSCs derived from aged rats fail to undergo adipogenic, chondrogenic, osteogenic and cardiomyogenic differentiation. BM-MSCs derived from young rats transform into fat-forming adipocytes, cartilage-forming chondrocytes, bone-forming osteocytes and cardiomyogenic cells. BM-MSCs were isolated from ‘aged’ and ‘young’ Sprague Dawley rats (15 months and 4 months).

Figure 2

Diagrammatic illustration of potential factors that feed into the bone marrow-derived mesenchymal stem cell (BM-MSC) niche. Diminished BM-MSC function associated with natural aging may be due to deleterious changes at the niche level. Different factors that regulate and maintain the local BM-MSC microenvironment are depicted. Within the niche, BM-MSCs are responsive to metabolic factors and their products, such as oxidative stress and reactive oxygen species (ROS). Paracrine and signaling factors such as Notch, transforming growth factor (TGF)-β, mitogen-activated protein kinase (MAPK), Wnt and NF-ĸB are known to be age dysregulated in the stem cell niche. Physical and environmental factors such as space constraints, and cell-cell interactions between BM-MSCs and other stem and non-stem cells resident in the bone marrow, and between BM-MSCs and the local extracellular matrix may undergo age-associated changes. In response to these changes, BM-MSCs are likely to undergo molecular level changes, such as increased levels of pro-aging factors, DNA damage, telomerase attrition and transcription factor changes. The direct consequence of these changes is diminished BM-MSC function, self-renewal and differentiation capacity. ECM, extracellular matrix; HSC, hematopoietic stem cell.