Control of Adult Stem Cell Function in Bioengineered Artificial Niches

A healthy diet improves adult stem cell function and delays diseases such as cancer, heart disease, and neurodegeneration. Defining molecular mechanisms by which nutrients dictate stem cell behavior is a key step toward understanding the role of diet in tissue homeostasis. In this paper, we elucidate the mechanism by which dietary cholesterol controls epithelial follicle stem cell (FSC) proliferation in the fly ovary. In nutrient-restricted flies, the transmembrane protein Boi sequesters Hedgehog (Hh) ligand at the surface of Hh-producing cells within the ovary, limiting FSC proliferation. Upon feeding, dietary cholesterol stimulates S6 kinase–mediated phosphorylation of the Boi cytoplasmic domain, triggering Hh release and FSC proliferation. This mechanism enables a rapid, tissue-specific response to nutritional changes, tailoring stem cell divisions and egg production to environmental conditions sufficient for progeny survival. If conserved in other systems, this mechanism will likely have important implications for studies on molecular control of stem cell function, in which the benefits of low calorie and low cholesterol diets are beginning to emerge.

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The BAF53a subunit of SWI/SNF-like BAF complexes is essential for hemopoietic stem cell function

Blood ◽

10.1182/blood-2012-04-427047 ◽

2012 ◽

Vol 120 (24) ◽

pp. 4720-4732 ◽

Cited By ~ 62

Author(s):

Veneta Krasteva ◽

Manuel Buscarlet ◽

Abigail Diaz-Tellez ◽

Marie-Anne Bernard ◽

Gerald R. Crabtree ◽

...

Keyword(s):

Stem Cell ◽

Chromatin Remodeling ◽

Progenitor Cell ◽

Cell Function ◽

Adult Stem Cell ◽

Hemopoietic Stem Cell ◽

Conditional Deletion ◽

Chromatin Remodeling Complexes ◽

A Subunit

Abstract ATP-dependent SWI/SNF-like BAF chromatin remodeling complexes are emerging as key regulators of embryonic and adult stem cell function. Particularly intriguing are the findings that specialized assemblies of BAF complexes are required for establishing and maintaining pluripotent and multipotent states in cells. However, little is known on the importance of these complexes in normal and leukemic hemopoiesis. Here we provide the first evidence that the actin-related protein BAF53a, a subunit of BAF complexes preferentially expressed in long-term repopulating stem cells, is essential for adult hemopoiesis. Conditional deletion of BAF53a resulted in multilineage BM failure, aplastic anemia, and rapid lethality. These severe hemopoietic defects originate from a proliferative impairment of BM HSCs and progenitors and decreased progenitor survival. Using hemopoietic chimeras, we show that the impaired function of BAF53a-deficient HSCs is cell-autonomous and independent of the BM microenvironment. Altogether, our studies highlight an unsuspected role for BAF chromatin remodeling complexes in the maintenance of HSC and progenitor cell properties.

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Aldehyde dehydrogenase 1a1 is dispensable for stem cell function in the mouse hematopoietic and nervous systems

Blood ◽

10.1182/blood-2008-05-156752 ◽

2009 ◽

Vol 113 (8) ◽

pp. 1670-1680 ◽

Cited By ~ 70

Author(s):

Boaz P. Levi ◽

Ömer H. Yilmaz ◽

Gregg Duester ◽

Sean J. Morrison

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Aldehyde Dehydrogenase ◽

Cell Function ◽

Hematopoietic Cells ◽

Adult Stem Cell ◽

Aldh Activity ◽

Hematopoietic Stem ◽

Nervous Systems ◽

Adult Mice

Abstract High levels of aldehyde dehydrogenase (ALDH) activity have been proposed to be a common feature of stem cells. Adult hematopoietic, neural, and cancer stem cells have all been reported to have high ALDH activity, detected using Aldefluor, a fluorogenic substrate for ALDH. This activity has been attributed to Aldh1a1, an enzyme that is expressed at high levels in stem cells and that has been suggested to regulate stem cell function. Nonetheless, Aldh1a1 function in stem cells has never been tested genetically. We observed that Aldh1a1 was preferentially expressed in mouse hematopoietic stem cells (HSCs) and expression increased with age. Hematopoietic cells from Aldh1a1-deficient mice exhibited increased sensitivity to cyclophosphamide in a non–cell-autonomous manner, consistent with its role in cyclophosphamide metabolism in the liver. However, Aldh1a1 deficiency did not affect hematopoiesis, HSC function, or the capacity to reconstitute irradiated recipients in young or old adult mice. Aldh1a1 deficiency also did not affect Aldefluor staining of hematopoietic cells. Finally, Aldh1a1 deficiency did not affect the function of stem cells from the adult central or peripheral nervous systems. Aldh1a1 is not a critical regulator of adult stem cell function or Aldefluor staining in mice.

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