The Differentiation Balance of Bone Marrow Mesenchymal Stem Cells Is Crucial to Hematopoiesis

Abstract

Bone marrow mesenchymal stem cells (BMSCs), the important component and regulator of bone marrow microenvironment, give rise to hematopoietic-supporting stromal cells and form hematopoietic niches for hematopoietic stem cells (HSCs). However, how BMSC differentiation affects hematopoiesis is poorly understood. In this review, we focus on the role of BMSC differentiation in hematopoiesis. We discussed the role of BMSCs and their progeny in hematopoiesis. We also examine the mechanisms that cause differentiation bias of BMSCs in stress conditions including aging, irradiation, and chemotherapy. Moreover, the differentiation balance of BMSCs is crucial to hematopoiesis. We highlight the negative effects of differentiation bias of BMSCs on hematopoietic recovery after bone marrow transplantation. Keeping the differentiation balance of BMSCs is critical for hematopoietic recovery. This review summarises current understanding about how BMSC differentiation affects hematopoiesis and its potential application in improving hematopoietic recovery after bone marrow transplantation.

Figure 1

Osteogenesis and hematopoiesis. Distinct cell types in different stages of osteogenic differentiation form unique niches for hematopoietic cells. Osteoprogenitors secrete IL-7 and IGF-1 to support early-stage B lineage differentiation. Osteoblasts are indispensable for HSC maintenance. Immature osteoblasts participate in HSC expansion. Mature osteoblasts express DLL4, which binds to Notch receptor on T cell-competent common lymphoid progenitors (CLP) and induces thymic seeding. Osteocytes conduct lymphoid-supporting stroma and regulate HSPC mobilization.

Figure 2

Negative effect of bone marrow adipocytes on hematopoietic recovery. Adipogenic differentiation of bone marrow mesenchymal stem cells interferes the process of hematopoietic recovery after hematopoietic stem cell transplantation (HSCT). Adipocytic lineage, including APC (adipogenic progenitor cell), secretes DPP4 to cleave SDF-1. Moreover, BM adipocyte interacts with HSPCs to downregulate CXCR4 via NP-1, leading to a reduction in SDF-1/CXCR4 signaling and HSPS homing and engrafting. TGF-β1 secreted by BM adipocyte mediates cell-cycle arrest of HSPCs to inhibit HSPC expansion. Lipocalin 2 secreted by BM adipocyte inhibits erythropoiesis. DPP4 also cleaves hematopoietic factor including EPO, GM-CSF, G-CSF, and IL-3 to decrease their activity. Furthermore, BM adipocytes replace BMSCs and “pruning” sinusoids, resulting in a reduction of sinus caliber and hematopoietic activity. “Red” marrow then becomes “yellow” marrow in BM.

Figure 3

Stress condition-related pathways directly interfere with the differentiation of BMSCs. The differentiation of BMSCs is controlled by a complex signaling network. Runx2 and Osterix are key transcription factors in osteogenic differentiation. And PPARγ and C/EBPα are key transcription factors in adipogenic differentiation. However, aging, irradiation, and chemotherapy could cause a series of events and activate subsequent pathways. These pathways regulate key transcription factors Runx2 and PPARγ to lead to the shift of adipo-osteogenic balance.

Figure 4

Differentiation balance of mesenchymal stem cells and hematopoiesis. There is a reciprocality between osteogenesis and adipogenesis. Increased adipogenesis often leads to decreased osteogenesis, vice versa. BMSCs are exquisitely balanced for differentiation commitment. Modest osteogenesis of BMSCs promotes hematopoiesis. However, excessive adipogenesis impairs hematopoiesis. Keeping the adipo-osteogenic balance of BMSCs is therefore essential to bone hematopoiesis.