Stem Cell Biology

About Us

The research focus of the Department is primarily on pluripotent stem cells and their applications in reproductive health and regenerative medicine (DOI: 10.1161/CIRCRESAHA.118.313823). The other major research focus of the group is on fertility issues of cancer patients/survivors.  Our focus gradually transitioned from pluripotent stem cells growing a Petri dish to those that exist in adult tissues.  These stem cells are termed very small embryonic-like stem cells (VSELs).

Very small embryonic-like stem cells (VSELs)

Tissue-resident, endogenous, pluripotent VSELs exist in multiple adult tissues (DOI: 10.1007/s12015-019-09879-2) and we have studied them in details in cord blood, bone marrow, testis, ovary, pancreas, uterus.  VSELs express pluripotent markers and also have the ability to differentiate into 3 germ layers (DOI: 10.1007/s12015-016-9714-0).  LIN-CD45- VSELs can also differentiate into LIN-CD45+ HSCs and germ cells. VSELs do not divide readily in vitro and survive both radiotherapy in mouse bone marrow and chemotherapy in the testes and ovaries. VSELs also survive in atrophied mouse uterus after bilateral ovariectomy. Developing strategies to exploit regenerative potential of endogenous VSELs may be the best approach to achieve regeneration.

Whether VSELs exist or not in adult tissues has remained a matter of dispute.  We can now enrich VSELs from any tissue by first centrifuging the cells suspension obtained after enzymatic digestion at 200-300 g when majority of cells pellet down (and stem cells remain buoyant) followed by centrifuging the supernatant at 1000g to pellet the stem cells. We obtained 10 folds enrichment of stem cells from adult mouse testes using this protocol (DOI: 10.1093/humupd/dmz030) and also from the mouse uterus (DOI: 10.1007/s43032-020-00250-2) and pancreas (DOI: 10.1007/s12015-019-09919-x).  This robust method can be replicated in any lab to confirm presence of VSELs.

VSELs and Regenerative Medicine

VSELs that survive oncotherapy in the gonads can be manipulated to regenerate non-functional gonads of cancer survivors and aged couples desiring to have biological parenthood (DOI: 10.4103/ijmr.IJMR_2065_17).

We reported VSELs (DOI: 10.1007/s12015-019-09919-x) in intact pancreas and also in the beta islets of adult mouse pancreas.  Flow cytometry data showed that VSELs almost double in numbers in the diabetic mouse pancreas after streptozotocin treatment and further when diabetic pancreas is subjected to partial pancreatectomy. But they are unable to differentiate and ameliorate diabetic symptoms by differentiating into healthy islets as the stem cells niche gets affected by STZ treatment.  Transplanting niche cells could reverse diabetic symptoms.

VSELs and Reproductive Health

Incidence of infertility and various diseases associated with reproductive health including fibroids, endometriosis, polycystic ovarian syndrome, premature ovarian failure and cancers have increased in recent past and a general reduction in sperm count.  However, none of the omics approaches have yet explained etiology of any of these pathological conditions. It is generally concluded that these conditions are multifactorial disorders where gene-gene interaction or gene-environment interactions further complicate the analysis.  Life-long tissue homeostasis is maintained by resident stem cells and any aberration to the stem cells compartment leads to diseased state.  It is most likely that these reproductive health related diseases have a stem cell basis.

Testicular stem cells

We recently showed that altered biology of testicular VSELs by exposing mouse pups to endocrine disruption could result in reduced sperm count, infertility and testicular cancer (DOI: 10.1007/s12015-020-09996-3;  https://link.springer.com/article/10.1007/ s12015-020-10030-9).

Uterine stem cells

Adult mouse harbors two populations of stem cells including VSELs and ‘progenitors’ endometrial stem cells (EnSCs).  These were studied across different stages of estrus cycle and in endometrial, stromal and myometrial compartments.  They were characterized in-depth and express receptors for ERα, ERβ, PR and FSHR (DOI: 10.1007/s43032-020-00250-2).

Age-related changes in mouse bone marrow VSELs and HSCs

Cellularity of marrow decreases and although VSELs possess the ability to proliferate in response to stress, their ability to differentiate gets compromised with age.  We have recently shown that in young mice, VSELs and HSCs respond to stress, restore homeostasis and return to basal numbers however, their response to stress gets affected with age. VSELs/HSCs increase in numbers and remain elevated while their differentiation is affected in aged marrow.  This tendency to proliferate and compromised differentiation explains increased incidence of leukemia noted in adult population and transplantation of paracrine providing niche cells – mesenchymal cells in aged marrow- restores hematopoiesis (DOI: 10.1007/s12015-020-09998-1).

People

Department Email Id: stemcell@nirrh.res.in

Projects

Ongoing Projects

1. Role of histone modifiers during differentiation of human embryonic stem cells into cardiac lineage (PI: Deepa Bhartiya) Funded by CSIR 2016-2019
2. Detailed Characterization of VSELs and demonstration of their efficacy in preclinical and clinical settings (PI: Deepa Bhartiya) Funded by ICMR 2016-2018