Polarized cells, polarized views: asymmetric cell division in hematopoietic cells

Abstract

It has long been recognized that alterations in cell shape and polarity play important roles in coordinating lymphocyte functions. In the last decade, a new aspect of lymphocyte polarity has attracted much attention, termed asymmetric cell division (ACD). ACD has previously been shown to dictate or influence many aspects of development in model organisms such as the worm and the fly, and to be disrupted in disease. Recent observations that ACD also occurs in lymphocytes led to exciting speculations that ACD might influence lymphocyte differentiation and function, and leukemia. Dissecting the role that ACD might play in these activities has not been straightforward, and the evidence to date for a functional role in lymphocyte fate determination has been controversial. In this review, we discuss the evidence to date for ACD in lymphocytes, and how it might influence lymphocyte fate. We also discuss current gaps in our knowledge, and suggest approaches to definitively test the physiological role of ACD in lymphocytes.

Keywords: asymmetric cell division; cell fate; cell polarity; immunological synapse; scribble complex.

Figure 1

Asymmetric cell division in solid tissues of (A) Drosophila, (B) C. elegans, and (C) Mammals. (A) In Drosophila, selected neuroblasts undergo up to 20 rounds of asymmetric cell division (ACD). The asymmetric distribution of polarity and cell fate determinants causes spindle asymmetry to result in a large self-renewing neuroblast cell and a smaller ganglion mother cell (GMC). The GMC undergoes a subsequent ACD to produce a glial cell and a neuron. (B) ACD during zygotic division in C. elegans. The site of sperm entry serves determines the asymmetric distribution of polarity and cell fate determining proteins as well as spindle asymmetry. During the embryonic stage four rounds of ACD results in the emerging anterior body (AB) and posterior (P) cells. During the larval stage, 53 somatic blasts undergo bursts of ACD and symmetric cell division (SCD), specifying all future posterior or soma fates in various tissues. (C) Neuronal precursor asymmetric division in mammals. The first asymmetric cell division produces a neuron and an intermediate neuronal precursor (INP), which undergoes a symmetric division to produce two neurons.

Figure 2

The three requirements of asymmetric cell division. For control of progeny proliferation, death, and differentiation during asymmetric cell division ACD, three requirements must be fulfilled; (1) an anchor to dictate the axis of polarity, in this case another cell; (2) the dividing cell is aligned along the axis of division, usually perpendicular to the anchor (perpendicular orientation shown by the alignment of mitotic spindle, red); and (3) that polarity of the protein (green) is maintained throughout division.

Figure 3

Models of asymmetric cell division in (A) Drosophila neuroblasts, (B) hematopoietic stem cells, (C) B cells, and (D) T cells. (A) In Drosophila, neuronal precursors delaminate from the neurepithelium to undergo ACD. The polarity cue is the apical crescent, and during early division duplicated centrosomes rotate 90° to create the distinct apical and basal sides that are mediated by the Scribble and Bazooka polarity protein complexes. During late division, the coordination of the spindle length by Gα_i signaling and proteins such as Inscuteable and Pins result in asymmetric distribution of cell fate determinants, such as Numb, Notch, Brat, and Prospero. The coordination and maintenance of signaling results in a self-renewing neuroblast cell and a ganglion mother cell (GMC). In cells of the hematopoietic system, multiple polarity cues can dictate asymmetric cell division. (B) Hematopoietic stem cells migrating in a stem cell niche in the bone marrow can receive adhesion, Notch or chemokine cues from surrounding endothelial, osteoblast, or sinusoidal cells, resulting in asymmetric distribution of cell fate determinants such as Notch and Numb (during attachment with the interacting cell or separately) to produce a self-renewing hematopoietic stem cell and a hematopoietic progenitor cell, which will go on to differentiate. In (C) B cells and (D) T cells the polarity cue might be through interaction with macrophages, other T cells and antigen presenting cells such as dendritic cells via adhesion, chemokine, or TCR molecules. This interaction sets an axis of division and asymmetric distribution of several surface molecules, antigen polarity, and cell fate determinants. In B cells daughters proximal to the interacting cells favor memory B cell fate, as well as more potent T cell activators and proliferators. Distal B cell daughters favor antibody secreting cell fate, with moderate T cell activating and proliferative capabilities. In the absence of ICAM-1, B cell fate is altered toward memory B cells at the expense of antibody secreting B cells. T cell daughters will inherit factors that will increase or decrease their propensity to adopt a variety of fates including that of a memory or effector T cell.

Figure 4

Outstanding questions for ACD.