Cellular and Molecular Basis of Histogenesis

About the Lab

Hematopoietic and immune cells play a pivotal role in the support of host homeostasis. Their dysfunction underlies many pathologies, including autoimmune, infectious, hereditary, vascular, oncological, and other conditions.

N. G. Khrushchev
(1932 - 2009).

The main interest of our laboratory is to gain insight into the mechanisms of hematopoietic development in steady-state and pathological conditions. We are specifically interested in intercellular interactions and intracellular molecular pathways that regulate inflammatory and antibacterial immune responses of innate immune cells, and in the development of cell therapy approaches based on the use of myeloid cells.

Our current studies continue and extend research that was undertaken in the laboratory when it was first founded in 1971 and headed by the famous Russian biologist N. G. Khrushchev.

Research fields

Figure 1. HSC expansion and iPSC differentiation into macrophages and MDSCs.

Main current research projects and topics:

— Developing a model to generate human macrophages from induced pluripotent stem cells;
— Developing gene-targeted approaches to regulate inflammatory and antibacterial responses of human macrophages;
— Deciphering the mechanisms underlying the generation and functional activity of myeloid-derived suppressor cells;
— Testing different conditions allowing the expansion and differentiation of hematopoietic stem cells (HSCs).

In our macrophage studies we use a model of macrophage differentiation from induced pluripotent stem cells (iPSCs) (Fig. 1, 2).

This allows to model tissue-residing macrophages and generate gene-edited macrophages (Fig. 2).

Figure 2. Main stages of macrophage differentiation from human iPSCs: iPSCs (А), Embryoid bodies (В), Macrophages (C).

We have recently demonstrated that iPSC-derived macrophages (iMphs) exhibit the typical macrophage morphology, express macrophage phenotype, and are highly phagocytic (Nenasheva et al., 2020). We are currently using this model to decipher the role of several specific genes in the regulation of macrophage protective and inflammatory responses. The long-term goal of the studies is to develop new therapeutic approaches to treat pathologies associated with macrophage dysfunction (Fig.3).

Figure 3. Main current and prospective iMph applications. Since the development of iMph generation techniques, the spectrum of iMphs applications has rapidly grown. Starting with the modeling of hereditary diseases associated with impaired macrophage function, it currently also includes the modeling of macrophage-pathogen interactions, drug testing and screening and the development of approaches to iMph-based cell therapy. BS Blau syndrome, CGD chronic granulomatous disease, CINCA chronic infantile neurologic cutaneous and articular syndrome; DENV Dengue virus, FMF familial Mediterranean fever, GD Gaucher disease, HTS high throughput screening, IBD inflammatory bowel disease, Mtb Mycobacterium tuberculosis, PAP pulmonary alveolar proteinosis, PD Parkinson’s disease, TD Tangier disease, ZIKV Zika virus.

From: Lyadova, I., Vasiliev, A. Macrophages derived from pluripotent stem cells: prospective applications and research gaps. Cell Biosci 12, 96 (2022). DOI.

Figure 4. MSCs of rat adipose tissue on scaffold from alkaline soluble collagen. Total preparation.

Our second interest focuses on MDSCs, a heterogeneous population of immature myeloid cells able to regulate/suppress immune response (Fig. 1). MDSCs are implicated in the progression of many diseases, including cancer, infectious diseases, and autoimmune disorders, but the mechanisms regulating their generation and function, as well as their precise role in many pathologies are not fully understood. We previously reported the impact of MDSCs in the progression of tuberculosis infection in an experimental TB model in mice and humans (Lyadova et al., 2010; Tsiganov et al., 2014; Panteleev et al., 2017). Currently, we are planning to use in vitro and in vivo models to decipher the factors and mechanisms that determine MDSC generation and suppressor activity in steady-state conditions and in response to inflammation.

Hematopoietic stem cells represent an important source for the cell therapy of blood system diseases. Their wide usage is currently limited by the lack of compatible donors and the absence of methods for HSC expansion ex vivo. We are currently starting pilot experiments to test different methods of HSC expansion and differentiation in vitro (Fig.4).

The lab members

Irina Lyadova

M.D., PhD, Head of the Lab

Research Interests: the regulation of host antibacterial response and inflammation; hematopoiesis in steady-state and pathological conditions; infectious immunology; cell therapy.