Tippi Mackenzie, MD

Associate Professor
Department of Surgery
Research Overview: 

Fetal surgery was developed at UCSF over 30 years ago as a way of treating select fatal congenital anomalies.  While it has helped hundreds of children with severe anatomic disorders, it is clear that if we could develop safe and effective means of transplanting stem cells into the fetus, we could further transform this field by broadening its scope of diseases.  For example, in utero stem cell transplantation can be used to treat diseases in which stem cells are missing or mutated, such as immunodeficiencies, inborn errors of metabolism, or muscular dystrophy Research in our lab is focused on developing safe and effective stem cell transplantation and other therapies for fetuses with congenital anomalies.

The fetal environment is particularly fertile ground for the success of stem cell transplantation.  We and others have shown that transplanted cells migrate widely in the fetal environment and show enhanced capacity for differentiation.  The main advantage of this strategy is that early in gestation, the fetus is immunologically immature, which gives an opportunity to transplant allogeneic or xenogeneic cells without an immune response. Donor-specific tolerance induction has been achieved in multiple animal models, allowing repeat stem cell or organ transplantation in the postnatal period.  However, clinical applications have been hampered by low engraftment, which has led us to reconsider potential barriers to success.  One conundrum is that while the fetus is widely regarded as immunologically naïve, there is evidence that transplanted cells are sometimes rejected.  Our hypothesis is that trafficking of cells between the mother and fetus may influence the immune response to transplantation.  We have recently found that it is the maternal, not fetal immune system that rejects the cells we transplant into the fetus.  We are therefore studying the mechanisms by which this happens as a way to develop strategies to overcome the immune response.  These experiments are performed in a mouse model of fetal stem cell transplantation that is routine in our lab. 

We are also exploring the role of maternal/fetal immune responses as a mechanism of preterm labor in patients undergoing fetal surgery or who have preterm labor from other causes. Preterm birth occurs in about 12% of all pregnancies in the United States and is the leading cause of neonatal morbidity and mortality in the developed world. The effects of premature birth can be devastating throughout the child's life. While inflammation in particular (both as a result of maternal infection and in the context of fetal infection) is widely regarded as being causative for preterm labor, the precise mechanisms leading from inflammation to preterm parturition have not been defined.  We are studying cellular trafficking between the mother and her fetus and its role in the etiology of inflammation-induced preterm labor. We hypothesize that preterm labor may involve alterations in trafficking that could lead to the breakdown of tolerance between the mother and the fetus. We are also exploring the role of maternal T cells in preterm labor in both our mouse model and in patients with preterm labor after fetal surgery.  If we determine that altered trafficking and maternal immune responses are causative in preterm labor, these findings will bring new paradigms for understanding and treating this devastating disease.  We are also studying the pathophysiology of prenatally diagnosed diseases such as congenital diaphragmatic hernia and gastroschisis to identify biomarkers that predict prognosis and molecular pathways that may be targets for prenatal intervention. Thus, research in our lab addresses several important clinical questions by using an array of methods from mouse models to humans.

Primary Thematic Area: 
Secondary Thematic Area: 
Developmental & Stem Cell Biology
Research Summary: 
Tolerance induction after in utero stem cell transplantation or gene therapy



Sacrococcygeal teratoma: late recurrence warrants long-term surveillance.

Pediatric surgery international

Padilla BE, Vu L, Lee H, MacKenzie T, Bratton B, O'Day M, Derderian S

Fetal stem cell and gene therapy.

Seminars in fetal & neonatal medicine

Witt R, MacKenzie TC, Peranteau WH

Epidemiology of Live Born Infants with Nonimmune Hydrops Fetalis-Insights from a Population-Based Dataset.

The Journal of pediatrics

Steurer MA, Peyvandi S, Baer RJ, MacKenzie T, Li BC, Norton ME, Jelliffe-Pawlowski LL, Moon-Grady AJ

Favorable Outcomes After In Utero Transfusion in Fetuses with Alpha Thalassemia Major - A Case Series and Review of the Literature.

Prenatal diagnosis

Kreger EM, Singer ST, Witt RG, Sweeters N, Lianoglou B, Lal A, Mackenzie TC, Vichinsky E

A Transient Developmental Hematopoietic Stem Cell Gives Rise to Innate-like B and T Cells.

Cell stem cell

Beaudin AE, Boyer SW, Perez-Cunningham J, Hernandez GE, Derderian SC, Jujjavarapu C, Aaserude E, MacKenzie T, Forsberg EC