Development

How is hematopoiesis regulated by mechanics?

Once blood circulation is established during the earliest stages of hematopoiesis, the pulsatile nature of blood flow within the aorta generates a range of biomechanical forces, such as fluid shear stress, hydrodynamic pressure, and circumferential stress. A number of studies have shown that the hemodynamic environment within the blood vessels has a direct influence on the structural and functional characteristics of the endothelial cells lining the inner walls of the vascular tissue (reviewed [1]).

Based on these findings, a number of research groups speculated that biomechanical forces might also be required during the development of the hematopoietic system. This was supported by the close association between the development and the anatomical locations of endothelial and hematopoietic lineage forming tissue in the embryo. When embryoid body cells derived from mouse embryonic stem cells were exposed to fluid shear stress at a magnitude that is comparable to the forces acting under physiological conditions, the embryoid body cells upregulated expression of CD31 protein, which is a molecular marker of endothelial and hematopoietic cell lineages, as well as upregulation of Runx1 transcription factor for hematopoiesis. These molecular changes had direct functional implications, since shear stress-exposed cells showed a greater tendency to form hematopoietic precursor colonies. Similar findings were obtained using in vitro cultures of the P-Sp and AGM regions, as exposure of these embryonic tissues to shear stress increased their hematopoietic potential. Moreover, these cells showed an inclination to differentiate into specific lineages, particularly B-lymphoid and erythroid lineages, under the influence of physical stimuli [2].

In the bone marrow, which are the long-term hematopoietic sites in adult organisms, discrete microenvironments called niches exist. The niches are defined by the mechanical properties of the matrix, and by their distinct biomolecular and cellular profiles [3]. The dynamic interactions that occur between the HSCs and the marrow niches are responsible for maintaining hematopoietic stem cell populations as well as for fate determination of these HSCs [4][5][6]. For instance, endosteal niches located near the bone surface contain inactive, long-lived HSCs, while perivascular niches located deep inside the marrow house active, self-renewing, short-lived HSCs [7][8]. The influence of the mechanical properties on bone marrow hematopoiesis were demonstrated by a study that used extracellular matrix protein-coated polyacrylamide substrates to mimic distinct marrow niches. Mouse HSCs grown on substrates of increasing stiffness underwent a change in morphology from a circular to a polarized shape, and their rate of proliferation also increased. More interestingly, the study reported that the matrix stiffness (which was modulated by the ligand composition) had a direct impact on the lineage determination of these HSCs. Substrate stiffness was modulated depending on ligand composition. At endosteal niches, a stiffer microenvironment due to higher concentrations of fibronectin led to less-differentiated early stage hematopoietic progenitors. However, softer perivascular niches containing high levels of laminin promoted the differentiation of the progenitor cells into myeloid lineages. Intracellular tension generated by actin–myosin contractility was shown to further compliment the fate-determining capacity of the extracellular biophysical cues [9].

A large number of blood disorders, ranging from non-malignant conditions such as anemia and thalassemia to malignant disorders such as lymphoma and leukemia, affect the human population. It is therefore becoming increasingly essential to gain deeper insights into the mechanisms that regulate the proliferation, self-renewal, and lineage commitment of HSCs, so as to be able to better understand the pathophysiology and the molecular-level dysregulation underlying many of these conditions. The ability of HSCs to repopulate the entire hematopoietic system of an organism has made them invaluable tools for the treatment of a number of hematological disorders. In recent decades, the regeneration of the hematopoietic system through bone marrow transplantations has become a routine therapeutic approach in treating patients suffering from debilitating blood disorders [10][11][12]. Recent research highlighting the regulatory role of the bone marrow niches during hematopoiesis have provided a basis for the in vitro development of optimized biomaterial platforms for the maintenance and differentiation of HSCs that could be used as analytical tools for monitoring real-time functional changes in HSCs.

References

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