Mesenchymal stem/progenitor cells promote the reconstitution of exogenous hematopoietic stem cells in Fancg−/− mice in vivo

Abstract

IntroductionThe microenvironment represents a defined anatomical compartment that provides regulatory signals to hematopoietic stem/ progenitor cells (HSPCs) via interactions with the microenvironment as a 3-dimensional matrix of cells, extracellular matrix molecules, and cell-bound or soluble cytokines and chemokines. [1][2][3][4][5][6] The essential cellular component of this microenvironment, also termed as the "niche," is derived from a common progenitor of mesenchymal origin 7 that gives rise to osteoblasts, self-renewing osteoprogenitors, 3,[8][9][10][11][12] and endothelial cells lining sinusoids. 13 These mesenchymal stem/progenitor cells (MSPCs) express/secrete the cytokines, extracellular matrix proteins, and cell adhesion molecules that support the homing, migration, proliferation, and survival of HSPCs in vitro and in vivo. 8,[14][15][16][17] Given the functional importance of the microenvironment, there has been significant experimentation to test the hypothesis that transplantation of various stromal elements will enhance the engraftment of hematopoietic stem cells. However, despite the unambiguous role for stromal elements in supporting hematopoiesis, and the evidence that transplantation of mesenchymal cells enhances bone formation in patients with mesenchymal stem cell defects, 18 cotransplantation of mesenchymal cells has yielded only modest and variable enhancement to the engraftment of hematopoietic stem cells (HSCs). The use of genetic models that have defects in hematopoietic and/or mesenchymal stem cells may facilitate characterizing the role of MSPCs in supporting hematopoiesis.Fanconi anemia (FA) is a complex recessive inherited disorder caused by mutations in 13 genes whose products interact in a common pathway associated with the homologous recombination repair of DNA damage. [19][20][21][22] Patients with FA are clinically characterized by congenital anomalies, a progressive bone marrow failure, and a high propensity to develop malignancies. [19][20][21][23][24][25][26] Although it is established that FA has defects in the HSC compartment, the effect of loss of FA in other stem cell compartments has received relatively limited attention. In particular, other than variable cytokine production by FA fibroblasts and limited coculture experiments with variable results conducted more than 13 years ago, 24,25,27,28 little information is available on the role of FA genes in influencing mesenchymal lineage functions and fates. However, the fact that patients with FA have characteristic anomalies in the skeletal, renal, and cutaneous tissues, all of which are mesenchymal derived, provides a strong rationale for exploring the role of FA genes in MSPC functions that provide good model systems in vitro and in vivo in syngeneic murine models of FA.In the present study, we investigated the effect of MSPCs in modulating HSPC functions both in vivo and in vitro with the use of a murine model with targeted disruption of the Fancg gene (Fancg Ϫ/Ϫ ), which has been shown to be hypersensitive in vivo to ...

Disruption of Bis Leads to the Deterioration of the Vascular Niche for Hematopoietic Stem Cells

“…Moreover, alterations in microenvironmental factors including changes in the cellular mass of the niche [3,4,11] or their interaction with HSCs [9] are responsible for concomitant changes in the HSC pool or various hematopoietic derangements such as hematopoietic failure [37] or myeloproliferative disease [8]. However, the understanding of the microenvironmental regulation is only now emerging and the signals or physiological factors that can influence the niche activities remain largely unknown.…”

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

“…Similarly, it has recently been reported that Fancg Ϫ/Ϫ mesenchymal stem/progenitor cells have defects in their ability to support the proliferation and differentiation of hematopoietic stem/progenitor cells. 41 Considering the crucial function of marrow environment in balancing stem cell self-renewal and differentiation, we propose this phenotype is very likely to contribute to the pathogenesis of FA. Despite the marked reduction in HSC and progenitor numbers and the reduced capacity for stem-cell function, Fancd2 Ϫ/Ϫ mice did not show spontaneous anemia in their peripheral blood and maintained relatively normal blood counts.…”

Role of endoplasmic reticulum stress in disuse osteoporosis

“…On day 14, cells were stained using a HEMA-3 quick staining kit (Fisher Scientific, Waltham, MA, USA). The number of CFU-F colonies with more than 50 cells was counted, and the clusters of cells that did not present fibroblast-like morphology were excluded [24,33,34].…”