Stem Cell Biology

About Us

The research focus of the Department is primarily on pluripotent stem cells and their applications in reproductive biology and regenerative medicine. The other major research focus of the group is on fertility issues of cancer patients/survivors.  Pluripotent stem cells include embryonic (hES) stem cells, induced pluripotent stem cells (iPS) and very small embryonic-like stem cells (VSELs).  Procedures to generate autologous human embryonic stem cell lines by somatic cell nuclear transfer (SCNT) have been standardized using sheep eggs. However, hES cells, iPS cells or SCNT derived hES cells grown in a Petri dish are not felt necessary any longer since pluripotent stem cells (see below) exist in various adult body organs. Work in the lab was initiated on hES cells and main focus has gradually shifted to VSELs.

 Embryonic stem cells

Two in-house derived human embryonic stem cell lines (KIND1 and KIND2) derived on human feeders are available and have also been adapted to feeder-free state. Both cell lines have good propensity to differentiate into mesoderm and endoderm. A pre-clinical study in mice was undertaken to evaluate the potential of hES cells derived pancreatic progenitors.  Studies are ongoing to understand epigenetic changes that are involved when ES cells become committed to a particular lineage with a focus on polycomb group proteins.  Microarray analysis was done to study how the transcriptome gets altered when hES cells differentiate into cardiomyocytes.

Very small embryonic-like stem cells (VSELs)

Endogenous, pluripotent VSELs have been studied in cord blood, bone marrow, testis, ovary, pancreas and uterus.  VSELs express pluripotent markers and also have the ability to differentiate into 3 germ layers.  They can also differentiate into HSCs and germ cells. Developing strategies to exploit regenerative potential of endogenous VSELs may be the best approach to achieve regeneration.

Being quiescent- VSELs survive in mouse gonads and bone marrow after chemo-ablation and can be targeted to regenerate the chemoablated gonads (restore fertility) (https://www.ncbi.nlm.nih.gov/pubmed/27663915; https://www.ncbi.nlm.nih.gov/ pubmed/27189070; as well as to reconstitute bone marrow (https://www.ncbi.nlm.nih. gov/pubmed/27095238).  VSELs are also involved during pancreas regeneration after partial pancreatectomy in mice (https://www.ncbi.nlm.nih.gov/pubmed/25976079). VSELs were recently reported in mouse uterine myometrium as possible stem cells that initiate formation of leiomyomas (https://www.ncbi.nlm.nih.gov/pubmed/28438190).

In contrast to the current understanding that only Sertoli cells in the testis and granulosa cells in the ovary express receptors for follicle stimulating hormone (FSHR), our work shows that FSHR are also expressed on the VSELs/ progenitors in various organs including testis, ovary, bone marrow and uterus. VSELs are stimulated by FSH and undergo asymmetric cell division whereby they undergo self-renewal and give rise to tissue specific progenitors.  Interesting this action is mediated through a novel FSHR transcript termed FSHR3 which has a putative exon 11 and lacks exon 10.

Besides showing presence of VSELs/OSCs in adult ovary – our group has also provided the mechanism whereby the stem cells are involved in neo-oogenesis and follicle assembly in adult ovary.  This is newly emerging understanding against the existing concepts that ovary has fixed number of eggs at birth and initial follicle growth is independent of FSH. We have also provided stem cell basis for menopause and ovarian cancer (https://www.ncbi.nlm.nih.gov/pubmed/25269615).  It is also possible to regenerate non-functional ovaries (https://www.ncbi.nlm.nih.gov/pubmed/28342456).

Better potential of VSELs compared to ES/iPS cells for regenerative medicine
Several groups across the world are attempting to make gametes from ES/iPS cells, but the field is stuck at the step to convert these stem cells into primordial germ cells (PGCs).  Thus the aim to obtain synthetic gametes from stem cells still remains a distant dream.  VSELs have the ability to spontaneously differentiate into gametes (https://www.ncbi.nlm.nih.gov/pubmed/25903688; https://www.ncbi.nlm.nih.gov/ pubmed/27868039; https://www.ncbi.nlm.nih.gov/pubmed/28070859) and thus are best option to obtain ‘synthetic gametes’.  The reason for better ability of VSELs to spontaneously form gametes is because they are indeed PGCs which survive in adult tissues (http://www.ncbi.nlm.nih.gov/pubmed/25421462).  This ability of VSELs has huge clinical relevance and our work is a major breakthrough (https://www.ncbi.nlm.nih.gov/pubmed/27244683).

Compared to ES/iPS cells which give rise to their fetal counterparts, VSELs show the ability to regenerate both acinar cells and islets in adult mouse pancreas after partial pancreatectomy.  Recently we discussed whether adult stem cells undergo reprogramming or VSELs get activated to account for plasticity, regeneration and cancer initiation (https://www.ncbi.nlm.nih.gov/pubmed/28631014).

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