Babes in the woods: Embryonic stem cells lose regenerative potential in aged microenvironments

I am a Californian, a biogerontologist, and a lifespan extension advocate, so it goes without saying that I’m a proponent of human embryonic stem cell (hESC) research. Sometimes, however, I feel like the discussion of hESCs’ therapeutic potential is a bit simplistic, and treats these complex and often cantankerous living entities as though they were some sort of passive magic elixir, which one must simply add to a system in order to achieve the desired effect.

Especially in the context of using hESCs to recover humans from age-related decline in tissue function, the situation is — while still promising — much thornier. A good deal of recent work suggests that the environment in which a stem cell resides (the “niche”) is at least as important to regenerative capacity as any property of the stem cell itself. A recent paper by Carlson and Conboy expands our knowledge of the deleterious effect of old niches on young cells; provides some tantalizing evidence of a mechanism, involving regulation of gene expression in the stem cells; and underscores the fundamental importance of studying the interaction between cells and their microenvironment.

Loss of stem cell regenerative capacity within aged niches

This work uncovers novel mechanisms of aging within stem cell niches that are evolutionarily conserved between mice and humans and affect both embryonic and adult stem cells. Specifically, we have examined the effects of aged muscle and systemic niches on key molecular identifiers of regenerative potential of human embryonic stem cells (hESCs) and post-natal muscle stem cells (satellite cells). Our results reveal that aged differentiated niches dominantly inhibit the expression of Oct4 in hESCs and Myf-5 in activated satellite cells, and reduce proliferation and myogenic differentiation of both embryonic and tissue-specific adult stem cells (ASCs). Therefore, despite their general neoorganogenesis potential, the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches. Significantly, this work establishes that hESC-derived factors enhance the regenerative potential of both young and, importantly, aged muscle stem cells in vitro and in vivo; thus, suggesting that the regenerative outcome of stem cell-based replacement therapies will be determined by a balance between negative influences of aged tissues on transplanted cells and positive effects of embryonic cells on the endogenous regenerative capacity. Comprehensively, this work points toward novel venues for in situ restoration of tissue repair in the old and identifies critical determinants of successful cell-replacement therapies for aged degenerating organs.

The most straightforward implication of Morgan and Conboy’s findings is that we will need to address the tissue microenvironment/niche/cell-cell signaling issues in order to optimize the therapeutic potential of hESCs introduced into an aged patient.

An obvious corollary is that identifying, targeting and inhibiting the “dominant” factors that decrease hESC pluripotency and proliferative capacity should be a major priority for scientists interested in developing stem-cell based solutions to the treatment of age-related disease.

(An aside about those quotation marks: I have a picky objection to the authors’ use in the abstract of the term “dominantly,” which I think should be reserved for relationships between alleles of the same gene: specifically, in which the dominant allele governs the phenotype regardless of the identity of the other allele. That said, I certainly know what they mean, and I further acknowledge that very new science is an undiscovered country to which a consistent nomenclature is often the last to arrive. The expression for an analogous relationship between different genes acting within the same pathway would be “epistatic”; I’m not at all sure what the term ought to be for a gene acting in one cell but having an effect on a neighboring cell.)

This work also demonstrates the growing utility of a concept from developmental biology: “non-cell-autonomous behavior,” in which some phenomenon (especially gene expression) acts “at a distance,” as it were, and causes a phenotype in another cell. This is as distinct from “cell-autonomous behavior,” in which the scope of a gene’s effect is limited to the cell that’s expressing it. Recently, I’ve increasingly noticed the use of the former term in discussions of a wide variety of findings, in both our lab and in others. I’d call it an important emerging theme in biogerontology.