Cells are Social Animals: peeping into the cell through its niche

Anjali AroraResearch Scholar

Indian Institute of Science Bangalore

“What’s the use of their having names,” the Gnat said, “if they won’tanswer to them?”“No use to them,” said Alice; “but it’s useful to the people that name them,I suppose.”

The Complete Works of Lewis CarrollThrough the Looking-Glass

Chapter III (p. 173)

Niche – a term borrowed from ecologyIn ecology, a niche describes a living thing’s specific interaction with its environment, more like a job description than an address.

Species Cells

Niche Breadth Niche partitioning Niche construction Niche differentiation

• Grinnellian niche- defined by the habitat and behaviour (1917)

• Eltonian niche- its relations to food and enemies (1927)

• Hutchinsonian niche- an n-dimensional hypervolume (1957) Charles Sutherland Elton

 Joseph Grinnell

 G. Evelyn Hutchinson

Consistent with the chaparral habitat Complentary physical traits (camouflaging color, short wings, strong legs)

"The niche relationships of the California Thrasher"

The Origin of the Niche Concept"Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells." Becker, Andrew J., Ernest A. McCulloch, and James E. Till (1963). "The relationship between the spleen colony-forming cell and the haemopoietic stem cell." Blood cells, Schofield, Raymond (1978).

Once ideas must be as broad as Nature if they are to interpret Nature.

• a defined anatomic site• a location where stem cells could be sustained and reproduce• a place where differentiation was inhibited• a limited space that also limited the numbers of stem cells• a place where reversion to a stem cell phenotype could be induced in a slightly more mature cell type

. “Decapentaplegic Is Essential for the Maintenance and Division of Germline Stem Cells in theDrosophila Ovary." Cell , Xie, Ting, and Allan C. Spradling (1998)"Somatic support cells restrict germline stem cell self-renewal and promote differentiation." Nature, Kiger, Amy A., Helen White-Cooper, and Margaret T. Fuller. (2000)

Niche – Different types

Stem cell niches

Niches

MammalsInvertebrate

Tumor niche

Bacterial/fungal niche

Plants

Bacterial/Fungal Niche

. "Bacterial strains isolated from different niches can exhibit different patterns of adhesion to substrata." Applied and environmental microbiology  Bakker, Dewi P., et al (2004)

. "Bacterial niche-specific genome expansion is coupled with highly frequent gene disruptions in deep-sea sediments." PloS one,  Wang, Yong, et al (2011):

. "Niche-specific requirement for Hyphal wall protein 1 in virulence of Candida albicans." PloS one , Staab, et al (2013)

Stem cell niches

Niches

MammalsInvertebrate

Tumor niche

Bacterial/fungal niche

Plants

Stem Cell

Stem cell niche structureECM proteins that provide structure, organization and mechanical signals to the niche

Stromal support cells- interact directly with the stem cell and with each other through cell-surface receptors, gap junctions and soluble factors

Blood vessels- that carry systemic signals and provide a conduit for recruitment of inflammatory and other circulating cells into the niche  

Neural inputs -distant physiological cues to the stem cell microenvironment 

•The stem cell niche exhibits an asymmetric structure•One daughter cell is maintained in the niche as a stem cell and the other daughter cell leaves the niche to proliferate and differentiate•Helps maintaining number of stem cells

•Organs contain a multitude of stem cell–niche units, which are often distributed across the entire expanse of the tissue

Why should a stem cell need a special environmentSupport Feedback

ControlInstruments of Coordination

Demanding Job

Communicating tissue status

Inter- lineageCoordination

Stem cell Niche- Invertebrate Models

• Two or three GSCs (Germ line Stem Cells) at the tip the ovariole

• In direct contact of cap cells• Daughter cell that remains in contact of cap cell

retains ‘stemness’• Number of GSCs correlate with the number of cap

cells

GSC Niche in Drosophila Ovary

GSC Niche in Drosophila Testis

• Seven to nine GSCs attached to hub cells• GSC divides asymmetrically, giving rise to one stem

cell and one gonialblast• SSCs also divide to generate two cyst cells, which

envelop the gonialblast

GSC Niche in C. ELEGANS• 225 germ cells closest to the distal tip cell (DTC) are

mitotic• Those further proximal are arrested in meiotic

pachytene• The somatic DTC is required for maintaining GSCs in

mitosisLi, et, al. (2005)

Stem cell Niche- Mammals

Li, et, al. (2005)

• The bulge area functions as a niche, where stem cells resides

• Shift of stem cells from quiescent to an activated state requires cues frm dermal papilla.

The hair follicle stem cell niche

• Limited number of stem cells at the crypt base

• Divide once a day symmetrically, daughter cell exit the stem cell compartment

• Paneth cells – daughter cell of the stem cell provide the stem cell niche signals

• What controls the number of Paneth cells is not known

The intestinal crypt niche

Stem cell Niche- Mammals

• HSCs physically attach to a subset of osteoblastic cells

• Jagged1 from osteoblasts, influences HSCs through the Notch receptor

• Number of  osteoblastic lining cells controls        the number of HSCs

• In vitro coculture of HSCs with osteoblasts can expand the HSC population

• Subventricular zone (SVZ) and the subgranular zone (SGZ) are germinal regions in which NSCs reside

• Endothelial cells provide attachment for SVZ and SGZ astrocytes and generate a variety of signals that control stem cell self-renewal and lineage commitment

Li, et, al. (2005)

Hematopoietic stem cell niche

The neural stem cell niche

Plant Niche•Plant stem cells function in a population mode-individual divisions are not strictly asymmetric

•Any given cell becomes a new stem cell or undergoes differentiation depends on its position

• Organizing center (OC) provides the nichefor stem cells in the shoot meristem

•Quiescent center (QC) functions as organizer of• the root stem cell niche

Tumor Niche - a disordered interaction•Cancer stem cells (CSCs),  a subpopulation of cells responsible for tumor initiation and formation reside in their own unique niche cancer stem cells niche

•Is cancer stem cell phenotype an unstable and context-dependent trait

•Cancer stem cells, do not depend solely on cell-intrinsic events but instead rely heavily on the right microenvironment – or niche

•Unlike normal stem cell niches, which have evolved for millions of years, cancer stem cells niche evolves in a remarkably short time 

•Loss of a niche environment mainly leads to the loss of  CSCs.

•Niche maintains the CSC pool, supports the growth of primary tumors, and plays a role in reverting nontumorigenic cells into CSCs by processes related to the EMT

Niche Evolution

Cancer stem cells in 

metastatic niches

Hypoxic Regions

Invasive fronts, perivascular sides

Normal stem cell niches- hijacked

Premetastatic niche must evolve in order for tumor cells to be able to engraft and proliferate at secondary sites

Metastatic niche model

Exploiting the Plasticity: Transdifferentiation•Somatic stem cells have been claimed to possess an unexpectedly broad differentiation potential – Plasticity•This could be induced by exposing stem cells to the extracellular developmental signals of other lineages in mixed-cell cultures – providing an appropriate niche

Wurmser, et. al. (2004)

What will happen if you put, stem cell ‘A’ into the niche of stem cell ‘B’?

Why we should know this?•To find out , if it really happening in our system•We can exploit this knowledge

Transplantation Endogenous TargetingIn vitro Modeling of Development and

Disease

Niche Concept Applications “Niche Market”

Ex-vivo CultureWith niche

Stem cell expansion

Stem cell loss

Without niche Alter nicheTransplantation

Untreated Expand

nicheLow Engraftment High

Engraftment

Biased production of certain cell types

Niche Concept Applications “Niche Market”

Endogenous Targeting

Dysfunction of niche

Loss of stem cells

Aging or Disease

Rejuvenation

Tumor regression

Delete /ModifyNiche cells

Niche Concept Applications “Niche Market”

In vitro Modeling of Development and

Disease

Stem cells alone

Differentiation

Stem cells + Normal niche

Differentiation

Stem cells + Diseased niche

Differentiation

Gene Modification/ Small Molecule

Gene Modification/ Small Molecule

• Whether an improved understanding of stem-cell microenvironments will provide clues about how to send stem cells down different developmental pathways, or reactivate quiescent stem cells?• Can understanding the niche provide novel strategies for more effectively delivering and engrafting transplanted stem cells?

• Can niche altering drugs support stem cells transplantation therapy

• How far a system’s equilibrium can be pushed before stem cells are wiped out or turn cancerous?• Differences between a normal stem cell, cancer stem cell, pre- metastatic

and metastatic niches?

• How a tumor cell alters its local and distant microenvironment?

• Can niche dysfunction be the cause of other diseases?

Niche of the future- Questions Unanswered

Thank You