Weimin Zhong, PhD

We seek to understand why stem cells in mammals cannot repair damages that go beyond the normal wear and tear, even though many mammalian tissues contain stem cells capable of producing differentiated cells to repair normal wears and tears to maintain tissue function throughout life. We hypothesize that multiple factors – through independent molecular pathways that regulate both the number and the temporal competence of stem cells – place fundamental constrains on their ability to repair tissue damages. Current research combines studies using Drosophila and mice to identify molecular components that specify the fates, count the number and regulate the competence of neural and other stem cells. We believe our studies will provide novel insights regarding the biology of stem cells, their therapeutic use in regenerative medicine and how cancers and neurodegenerative diseases like ALS and dementia arise.

Stem cells, whether of embryonic or adult origin, are defined by the abilityto produce more stem cells (self-renew) and the potential to generate differentiated offspring for carrying out tissue function. For stem cells involved in organogenesis and tissue maintenance, there is also an essential need to ensure a proper balance between self-renewal and differentiation, since a failure in either task will lead to organ malformation and tissue malfunction. How this is accomplished at the molecular and cellular level, however, remains poorly understood in mammals. Conceptually, stem cells can simultaneously self-renew and differentiate by dividing asymmetrically to produce one daughter cell that remains as a stem cell and another that differentiates. Stem cells, however, may also need to divide symmetrically to produce two stem cells, which can quickly expand their population when responding to a tissue injury, or to generate two differentiated cells, when large numbers of stem cells are no longer necessary towards the end of organogenesis and tissue repair. In other words, understanding the division patterns of stem cells – particularly how they are regulated under normal and pathological conditions – may facilitate a key goal of stem-cell research, which is to repair or replace damaged tissues by introducing exogenous stem cells or expanding endogenous populations.

Asymmetric cell division is a process by which a cell divides to produce two different daughter cells. Such divisions are widely used from invertebrates to mammals to generate cellular diversity during development and for stem cells to balance self-renewal and differentiation. In Drosophila, the Numb protein enables the two daughter cells to adopt different fates at birth after such divisions by localizing to only one side of a dividing precursor cell. Through a series of loss- and gain-of-function studies in mice, we show that Numb and Numbl are redundant but essential for embryogenesis and that asymmetric Numb localization in dividing neural stem cells is essential for generating the central nervous system. Our studies further reveal a novel cellular mechanism that uses Golgi fragmentation and reconstitution during mitosis, through changes in the subcellular distribution of an essential Numb partner, the ACBD3 protein, to coordinate cell-cycle progression and cell-fate specification during an asymmetric cell division.

(1) Probing the behavior of stem cells by changing their patterns of division
We have generated a set of unique mouse strains in which the division patterns of stem cells in various tissues can be differentially manipulated. We will use these mice to examine how stem cells behave under normal and pathological conditions in the nervous system and other tissues. By forcing stem cells to deviate from their normal patterns of division, we intend to identify key regulators of stem cells using molecular and genetic tools.

(2) Examining how cell fates are assigned to maintain tissue homeostasis
To maintain tissue homeostasis, stem cells have to generate differentiated cells of specific types, in correct numbers and at precise times. As a first step to understand how this is accomplished, we will combine studies using mice and Drosophila to elucidate the signaling pathway that enables Numb, ACBD3 and other partners to specify distinct daughter cell fates at birth during an asymmetric division, in particular how cellular signaling, epigenetic regulation and cell-cycle progression are coordinated.

(3) Examining how stem cells are regulated temporally
In the developing mammalian neocortex, neural stem cells change competence over time to sequentially produce six layers of functionally distinct neurons. Through a collaboration with scientists at Peking Union Medical College, we show microRNAs (miRNAs) are dispensable for stem-cell self-renewal and neuron production but essential for timing neocortical layer formation and specifying laminar fates in mice. We are examining how miRNAs determine temporal fates during neocortical neurogenesis.

(4) Using embryonic stem (ES) cells to probe human developmental mechanisms
We intend to examine whether the findings from our mouse studies are applicable to humans by determining whether Numb-mediated asymmetric cell divisions, as well as the signaling pathways that regulate stem-cell behavior, are used by human ES cells when they are induced to undergo neurogenesis in culture.