Intramarrow injection of β-catenin-activated, but not naïve mesenchymal stromal cells stimulates self-renewal of hematopoietic stem cells in bone marrow

Ji-Yeon Ahn,Jong-Wook Lee,Jae-Seung Shim,Il-Hoan Oh,Gyeongsin Park

doi:10.3858/emm.2010.42.2.014

Ji-Yeon Ahn, Jong-Wook Lee + Show 3 more

Open Access

https://doi.org/10.3858/emm.2010.42.2.014

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Abstract

Bone marrow mesenchymal stromal cells (MSCs) have been implicated in the microenvironmental support of hematopoietic stem cells (HSCs) and often co-transplanted with HSCs to facilitate recovery of ablated bone marrows. However, the precise effect of transplanted MSCs on HSC regeneration remains unclear because the kinetics of HSC self-renewal in vivo after co-transplantation has not been monitored. In this study, we examined the effects of intrafemoral injection of MSCs on HSC self-renewal in rigorous competitive repopulating unit (CRU) assays using congenic transplantation models in which stromal progenitors (CFU-F) were ablated by irradiation. Interestingly, naïve MSCs injected into femur contributed to the reconstitution of a stromal niche in the ablated bone marrows, but did not exert a stimulatory effect on the in-vivo self-renewal of co-transplanted HSCs regardless of the transplantation methods. In contrast, HSC self-renewal was four-fold higher in bone marrows intrafemorally injected with beta-catenin-activated MSCs. These results reveal that naive MSCs lack a stimulatory effect on HSC self-renewal in-vivo and that stroma must be activated during recoveries of bone marrows. Stromal targeting of wnt/beta-catenin signals may be a strategy to activate such a stem cell niche for efficient regeneration of bone marrow HSCs.

Highlights

Hematopoietic stem cells (HSC) are a rare cell population in the hematopoietic tissue that can sustain hematopoiesis throughout life and reconstitute bone marrows when transplanted into myeloablated recipients
To circumvent the barrier, we chose to directly introduce cultured mesenchymal stromal cells (MSC) expressing green fluorescent protein (GFP) into bone marrows by intrafemoral injection, and bone marrow cells harvested from recovered mice were examined for colony forming unit-fibroblast (CFU-F) colonies from the injected MSCs (GFP +)
No signs of myeloproliferative disease were seen in the transplanted mice. These results show that injection of β-catenin-activated MSCs stimulates HSCs without causing changes to normal bone marrow cellularity, suggesting that stromal activation of Wnt/β- catenin signals may be a strategy for targeting the stem cell niche to create a stimulatory bone marrow microenvironment

Summary

Introduction

Hematopoietic stem cells (HSC) are a rare cell population in the hematopoietic tissue that can sustain hematopoiesis throughout life and reconstitute bone marrows when transplanted into myeloablated recipients. The execution of self-renewal in transplanted HSCs may determine the efficiency of bone marrow reconstitution and recovery of stem cell pools. While several intrinsic regulators of HSC selfrenewal have been identified (Stein et al, 2004), recent studies have revealed a crucial role for the microenvironment in the self-renewal (Calvi et al, 2003; Zhang et al, 2003) and quiescence (Stier et al, 2005) of HSCs. The microenvironmental regulation of HSCs occurs in a specific architecture of the bone marrow stroma, called the stem cell niche. While the functional distinction between the two compartments remains unknown, it has recently been shown that mesenchymal stromal progenitors that can give rise to fibroblast colonies

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